Oxo-substituted compound

ABSTRACT

Provided is a novel compound that has an excellent β-lactamase inhibitory effect. More specifically, provided is a compound represented by formula (1a), (1b) or (11) having an excellent β-lactamase inhibitory effect or a pharmaceutically acceptable salt thereof. By using this compound either in combination with a β-lactam drug or alone, a useful preventive or therapeutic agent for bacterial infections is provided. Also provided are useful preventive or therapeutic agents for treating various diseases with the combined use of the aforesaid compound and β-lactam drugs.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 17/050,747, filed on Oct. 26, 2020, which is a national stage application of PCT/JP2019/018011, filed Apr. 26, 2019 which claims benefit of JP 2018-087761, the contents of each application is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to an oxo-substituted compound that is useful as a medicament or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a pharmaceutical composition comprising a novel oxo-substituted compound or a pharmaceutically acceptable salt thereof. The present invention relates to a therapeutic agent comprising the oxo-substituted compound or a pharmaceutically acceptable salt thereof.

BACKGROUND ART

Since the discovery of penicillin, antimicrobial agents have taken an important role in the treatment of infections.

In particular, β-lactam agents (e.g., penicillin antimicrobial agents, cephalosporin antimicrobial agents, and carbapenem antimicrobial agents) are agents that are most commonly used in the treatment of bacterial infections in view of their potent sterilizing capacity and high degree of safety. However, with increased use of β-lactam agents, emergence and prevalence of pathogenic bacteria that have acquired resistance to β-lactam agents have become a global problem. Examples of the mechanism of acquiring resistance of such pathogens include production of β-lactamase, structural change in the target molecule of a β-lactam agent, reduced drug permeation into microbial cell, elevated drug discharge, and the like. In particular, production of β-lactamase, which degrades and inactivates β-lactam agents, is one of the most influential in the maintenance of efficacy of β-lactam agents. Various bacteria are involved in the evolution of β-lactamase that antagonizes the efficacy of various β-lactam agents. β-lactamases can be classified into 4 classes based on their amino acid sequences, i.e., Ambler classes A, B, C, and D. Since class A, C, and D enzymes have a serine residue at the center of enzymatic activity, they are known as serine-sβ-lactamases. Since class B enzymes do not have a serine residue at the center of enzymatic activity but have metal ion zinc (Zn²⁺), they are known as metallo-s-lactamases (zinc-β-lactamases).

It has been already confirmed that concomitant use of a β-lactamase inhibiting agent and a β-lactam agent is effective for solving the problem of resistance acquisition due to production of β-lactamase. It is known that commercially available β-lactamase inhibiting agents clavulanic acid, sulbactam, and tazobactam primarily inhibit class A β-lactamases excluding KPC (Klebsiella pneumoniae Carbapenemase), and avibactam inhibits class A β-lactamases (including KPC), class C β-lactamases, and some class D β-lactamases including OXA-48 (Non Patent Literature 1). However, these existing β-lactamase inhibiting agents cannot effectively and broadly inhibit all β-lactamases produced by various bacteria. For example, such inhibiting agents do not exert an effect on class B metallo-β lactamases. Recently, β-lactamases called ESBLs (Extended Spectrum μ-Lactamases) that can degrade more substrates (β-lactam agent) compared to conventional β-lactamases were isolated, which have led to a problem as a new resistant bacteria, especially as a causative bacteria for hospital-acquired infections in the US and Europe. In addition, emergence and prevalence of metallo-β-lactamas producing bacteria is becoming a problem in Japan. In view of such a circumstance, it is very important to address β-lactamase producing bacteria including ESBLs and metallo-β-lactamase for the prophylaxis of hospital-acquired infections. Furthermore, pathogenic bacteria evolve quickly, such that emergence of new β-lactamase resistant bacteria is very likely. Accordingly, as a solution to such problems or as a safeguard against such issues to be addressed, there is a demand for the development of a novel β-lactamase inhibiting agent that has a different structure from existing β-lactamse inhibiting agents, whereby a broader β-lactamase inhibitory action or metallo-β-lactamase inhibitory action is expected.

Recently, boronic acid derivatives with β-lactamase inhibitory action have been reported in Patent Literatures 1 to 9 and the like. These Patent Literatures do not disclose a structure related to the oxo-substituted compounds encompassed by the present invention, i.e., a boronic acid compound group having a non-aryl heterocycle (preferably a nitrogen-containing non-aryl heterocycle) on a side chain at a specific position and an oxo substituent (—C(═O)—, —S(═O)—, —S(═O)₂—, or the like) that attaches to the ring.

CITATION LIST Patent Literature

-   [PTL 1] WO 2014/107535 -   [PTL 2] WO 2014/107536 -   [PTL 3] WO 2015/179308 -   [PTL 4] WO 2016/003929 -   [PTL 5] WO 2016/149393 -   [PTL 6] WO 2014/089365 -   [PTL 7] WO 2014/110442 -   [PTL 8] WO 2014/151958 -   [PTL 9] WO 2015/191907

Non Patent Literature

-   [NPL 1] Buynak. J D. Expert Opinion on Therapeutic Patents, 2013,     23(11), 1469-1481.

SUMMARY OF INVENTION Solution to Problem

The present invention provides a novel compound having excellent β-lactamase inhibitory action and provides a prophylactic or therapeutic agent that is useful for a bacteria infection, alone or in concomitant use with a β-lactam agent. Specifically, the present invention provides a prophylactic or therapeutic agent that is useful for therapy, by concomitant use with a β-lactam agent, of a disease such as sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, urinary tract infection, genital infection, eye infection, or odontogenic infection.

More specifically, the inventors completed the present invention by finding that a compound represented by formula (1a), (1b), or (11) described below or a pharmaceutically acceptable salt thereof (also referred to as the “compound of the invention” hereinafter) has excellent β-lactamase inhibitory action. Specifically, the present invention is the following.

[Item A1]

A compound represented by formula (1a) or (1b):

-   -   or a pharmaceutically acceptable salt thereof     -   wherein         -   G is an oxygen atom, a sulfur atom, or —NR^(a1)—,         -   X is a hydroxyl group, an optionally substituted C₁₋₆ alkoxy             group, or —NR^(a2)R^(b1),         -   R^(a1), R^(a2), and R^(b1) are the same or different, each             independently     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl,     -   6) a 4- to 10-membered non-aryl heterocycle,     -   7) a C₁₋₆ alkylcarbonyl group,     -   8) a C₃₋₁₀ alicyclic carbonyl group,     -   9) a C₆₋₁₀ arylcarbonyl group,     -   10) a 5- or 6-membered heteroarylcarbonyl group,     -   11) a C₁₋₆ alkylaulfonyl group,     -   12) a C₃₋₁₀ alicyclic sulfonyl group,     -   13) a C₆₋₁₀ arylsulfonyl group,     -   14) a 5- or 6-membered heteroarylsulfonyl group, or     -   15) —OR^(c1),     -   (wherein each substituent from 2) to 14) is optionally         substituted),         -   wherein R^(a2) and R^(b1) together may form an optionally             substituted 4- to 10-membered nitrogen-containing non-aryl             heterocycle,         -   R^(c1) is     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl, or     -   6) a 4- to 10-membered non-aryl heterocycle,     -   (wherein each substituent from 2) to 6) is optionally         substituted),         -   L¹ is a single bond, an oxygen atom, a sulfur atom, —SO—,             —SO₂—, —NR^(d)—, —NR^(d)C(═O)—, or —NR^(d)SO₂—,         -   L² is a single bond or an optionally substituted C₁₋₆             alkylene group,         -   Z is     -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) a carboxyl group,     -   5) a C₃₋₁₀ alicyclic group,     -   6) C₆₋₁₀ aryl,     -   7) 5- or 6-membered heteroaryl,     -   8) a 4- to 10-membered non-aryl heterocycle,     -   9) a C₁₋₆ alkoxy group,     -   10) a C₃₋₁₀ alicyclic oxy group,     -   11) a C₆₋₁₀ aryloxy group,     -   12) a 5- or 6-membered heteroaryloxy group,     -   13) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   14) a C₁₋₆ alkylthio group,     -   15) a C₃₋₁₀ alicyclic thio group,     -   16) a C₆₋₁₀ arylthio group,     -   17) a 5- or 6-membered heteroarylthio group,     -   18) a 4- to 10-membered non-aryl heterocyclyl thio group,     -   (wherein each substituent from 5) to 18) is optionally         substituted),     -   19) —SO₂—NR_(e1)R^(f1),     -   20) —NR^(e1)—C(═O)OR^(f1),     -   21) —NR^(g1)—C(═O)NR^(e1)R^(f1),     -   22) —NR^(e1)—C(═S)R^(f1),     -   23) —NR_(e1)—C(═S)OR^(f1),     -   24) —NR_(e1)—C(═S)NR^(e1)R^(f1),     -   25) —NR^(g1)—CR^(e1)(═NR^(f1)),     -   26) —NR^(g1)—CR^(e1)(═N—OR^(f1)),     -   27) —NR^(h1)—C(═NR^(g1))NR^(e1)R^(f1),     -   28) —NR^(h1)—C(═N—OR^(g1))NR^(e1)R^(f1),     -   29) —NR^(i1)—C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   30) —NR^(i1)—C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   31) —NR^(e1)—SO₂—R^(f1),     -   32) —NR^(g1)—SO₂—NR^(g1)R^(f1),     -   33) —C(═O)OR^(e1),     -   34) —C(═S)OR^(e1),     -   35) —C(═S)NR^(e1)R^(f1),     -   36) —C(═S)NR^(e1)OR^(f1),     -   37) —C(═S)NR^(g1)—NR^(e1)R^(f1),     -   38) —C(═NR^(e1))R^(f1),     -   39) —C(═N—OR^(e1)) R^(f1),     -   40) —C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   41) —C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   42) —NR^(e1)R^(f1),     -   43) —NR^(g1)—NR^(e1)R^(f1),     -   44) —NR^(e1)OR^(f1),     -   45) —NR^(e1)—C(═O)R^(f1),     -   46) —C(═O)NR^(e1)R^(f1),     -   47) —C(═O)NR^(e1)OR^(f1),     -   48) —C(═O)NR^(g1)—NR^(e1)R^(f1),     -   49) —C(═O)R^(e1),     -   50) —C(═NR^(g1))NR^(e1)R^(f1), or     -   51) —C(═N—OR^(h1))NR^(e1)R^(f1),         -   one of R¹, R², and R³ is a group represented by formula (2)

-   -   wherein         -   Y is an oxygen atom, a sulfur atom, or —NR^(j)—,         -   ring A is an optionally substituted 4- to 20-membered             non-aryl heterocycle,         -   L³ is —C(═O)—, —S(═O)—, or —S(═O)₂—,         -   L⁴ is     -   1) a single bond,     -   2) a C₁₋₆ alkylene group,     -   3) a C₃₋₁₀ cycloalkylene group,     -   4) a C₆₋₁₀ arylene group     -   5) a 5- or 6-membered heteroarylene group,     -   6) a 4- to 10-membered non-aryl heterocyclylene group, or     -   7) —C(═N—OR^(h1))—.     -   (wherein each substituent from 2) to 6) is optionally         substituted), and

R⁵ is

-   -   1) a hydrogen atom,     -   2) a C₁₋₆alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) a 4- to 10-membered non-aryl heterocycle,     -   5) C₆₋₁₀ aryl,     -   6) 5- or 6-membered heteroaryl,     -   7) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 2) to 7) is optionally         substituted), or     -   8) —NR^(e1)OH,         -   the remaining two (without the structure of formula (2)             among R¹, R², and R³) are the same or different, each             independently a hydrogen atom, a halogen atom, an optionally             substituted C₁₋₆ alkyl group, an optionally substituted C₁₋₆             alkoxy group, an optionally substituted C₁₋₆ alkylthio             group, an optionally substituted 5- or 6-membered             heteroaryl, or —NR^(e3)R^(b2),         -   R^(d), R^(e1), R^(e2), R^(f1), R^(f2), R^(g1), R^(g2),             R^(h1), R^(h2), R^(i1), R^(i2), and R^(j) are the same or             different, each independently a hydrogen atom, an optionally             substituted C₁₋₆ alkyl group, an optionally substituted             C₃₋₁₀ alicyclic group, optionally substituted C₆₋₁₀ aryl,             optionally substituted 5- or 6-membered heteroaryl, or an             optionally substituted 4- to 10-membered non-aryl             heterocycle,         -   a combination of R^(e1) and R^(f1) or R^(e2) and R^(f2),             when attached to the same nitrogen atom, together may form             an optionally substituted 4- to 10-membered             nitrogen-containing non-aryl heterocycle,         -   R⁴ is     -   1) —C(═O)R⁸,     -   2) —SO₂-L⁶-R⁸,     -   (wherein R⁸ in 1) and 2) is —NR^(a5)R^(b4),         —NR^(a5)-L⁷-B(OR^(e1))₂, —OR^(m1), or an optionally substituted         C₁₋₆ alkyl group, and L⁶ is a single bond or —NR^(a6)—),     -   3) —NR^(a4)R^(b3),     -   4) —B(OR^(m1))₂,     -   5) —PO(OR^(m1))(OR^(m2)),     -   6) optionally substituted 5-membered heteroaryl,     -   7) an optionally substituted 5-membered non-aryl heterocycle, or     -   8) a bioisostere of one of 1) to 7),     -   (wherein the formulas of 2), 4), 5), and 6) include a carboxylic         acid isostere, and 8) may include them in duplicates),         -   R^(a3), R^(a4), R^(a5), R^(a6), R^(b2), R^(b3), and R^(b4)             are the same or different, each independently having the             same definition as R^(a1), R^(a2), and R^(b1), wherein a             combination of R^(a3) and R^(b2), R^(a4) and R^(b3), or             R^(a5) and R^(b4), when attached to the same nitrogen atom,             together may form an optionally substituted 4- to             10-membered nitrogen-containing non-aryl heterocycle,         -   R^(m1) is     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl, or     -   6) a 4- to 10-membered non-aryl heterocycle     -   (wherein each substituent from 2) to 6) is optionally         substituted),         -   wherein if R^(m1) is attached to a boron atom via an oxygen             atom, two R^(m1), as C₂₋₄ alkylene, together with the boron             atom and two oxygen atoms, may form a 5- to 7-membered             non-aryl heterocycle (wherein an alkylene moiety is             optionally substituted in the non-aryl heterocycle),         -   R^(m2) is a hydrogen atom, an optionally substituted C₁₋₆             alkyl group, or an optionally substituted C₃₋₁₀ alicyclic             group, and         -   L⁷ is an optionally substituted C₁₋₃ alkylene group.

[Item A2]

The compound or the pharmaceutically acceptable salt thereof according to item A1, wherein

L¹ is a single bond, a sulfur atom, —NR^(d)C(═O)—, or —NR^(d)SO₂—,

L² is a single bond or an optionally substituted C₁₋₆ alkylene group, and

Z is

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl,     -   6) a 4- to 10-membered non-aryl heterocycle,     -   7) —C(═N—OR^(e1))R^(f1), or     -   8) —NR^(e1)R^(f1).

[Item A3]

The compound or the pharmaceutically acceptable salt thereof according to item A1 or A2, wherein

Z-L²-L¹ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted C₁₋₆ alkylthio group.

[Item A4]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A3, wherein Z-L²-L¹ is a hydrogen atom.

[Item A5]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A4, wherein G is an oxygen atom.

[Item A6]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A5, wherein X is a hydroxyl group or an optionally substituted C₁₋₆ alkoxy group.

[Item A7]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A6, wherein X is a hydroxyl group.

[Item A8]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A7, wherein the compounds of formulas (1a) and (1b) are represented by formulas (3a) and (3b), respectively:

wherein X, R¹, R², and R³ are defined the same as any one of items A1 to A7, and

R⁴ is selected from the group consisting of

-   -   1) —COOR^(m1) (wherein R^(m1) is a hydrogen atom, a C₁₋₆ alkyl         group, a C₃₋₁₀ alicyclic group, C₆₋₁₀ aryl, 5- or 6-membered         heteroaryl, or a 4- to 10-membered non-aryl heterocycle, and         wherein the C₁₋₆ alkyl group, the C₃₋₁₀ alicyclic group, the         C₆₋₁₀ aryl, the 5- or 6-membered heteroaryl, and the 4- to         10-membered non-aryl heterocycle are each optionally         substituted), and     -   2) a bioisostere of 1).

[Item A9]

The compound or the pharmaceutically acceptable salt thereof according to item A8, wherein R⁴ is

-   -   1) —COOH (i.e., a carboxyl group), or     -   2) a carboxylic acid isostere.

[Item A10]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A9, wherein the compounds of formulas (1a) and (1b) or the compounds of formulas (3a) and (3b) are represented by formulas (4a) and (4b), respectively:

wherein X, R⁴, Y, ring A, L³, L⁴, and R⁵ are defined the same as any one of items A1 to A9, and

-   -   R¹ and R² are the same or different, each independently a         hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, or a C₁₋₆         alkoxy group (wherein the C₁₋₆ alkyl group and C₁₋₆ alkoxy group         are optionally substituted with 1 to 5 halogen atoms).

[Item A11]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A10, wherein ring A is an optionally substituted 4- to 10-membered non-aryl heterocycle.

[Item A12]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A11, wherein ring A is an optionally substituted 4- to 7-membered non-aryl heterocycle.

[Item A13]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A12, wherein Y is an oxygen atom or a sulfur atom.

[Item A14]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A13, wherein Y is an oxygen atom.

[Item A15]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A14, wherein the compounds of formulas (1a) and (1b), the compounds of formulas (3a) and (3b), or the compounds of formulas (4a) and (4b) are represented by formulas (5a) and (5b), respectively:

wherein ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.

[Item A16]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A15, wherein L³ is —C(═O)— or —S(═O)₂—.

[Item A17]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A16, wherein L³ is —C(═O)—.

[Item A18]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A17, wherein L⁴ is a single bond, —C(═N—OR^(h1)) or an optionally substituted C₁₋₆ alkylene group, wherein R^(h1) is an optionally substituted C₁₋₆ alkyl group.

[Item A19]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A18, wherein L⁴ is a single bond, or a C₁₋₆ alkylene group optionally substituted with —NR²¹R²² or ═NOR²³, wherein R²¹, R²², and R²³ are each independently a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted 4- to 10-membered non-aryl heterocyclyl carbonyl group.

[Item A20]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A19, wherein L⁴ is a single bond, —CH₂—, —CH(NH₂)—, or —CH(NH₂)—CH₂—, wherein if an amino group is present in L⁴, carbon that attaches to the amino group attaches to L³.

[Item A21]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A20, wherein R⁵ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted 4- to 10-membered non-aryl heterocycle, optionally substituted C₆₋₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, an optionally substituted C₁₋₆ alkylthio group, or —NR^(e1)OH, wherein R^(e1) is a hydrogen atom or an optionally substituted C₁₋₆ alkyl group.

[Item A22]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A21, wherein R⁵ is optionally substituted 5- or 6-membered heteroaryl or optionally substituted C₆₋₁₀ aryl.

[Item A23]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A21, wherein L⁴ is a single bond, and R⁵ is —NR^(e1)OH, wherein R^(e1) is a hydrogen atom or an optionally substituted C₁₋₆ alkyl group.

[Item A24]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A22, wherein

R⁵ is selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(6a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) halogen,     -   5) a C₁₋₄ alkyl group,     -   6) a C₃₋₁₀ alicyclic group,     -   7) a C₁₋₄ alkoxy group,     -   8) a C₃₋₁₀ alicyclic oxy group,     -   9) a C₆₋₁₀ aryloxy group,     -   10) a 5- or 6-membered heteroaryloxy group,     -   11) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   (wherein each substituent from 5) to 11) is optionally         substituted),     -   12) —SO₂—NR^(e2)R^(f2),     -   13) —NR^(g2)—CR^(e2) (═NR^(f2)),     -   14) —NR^(g2)—CR^(e2) (═N—OR^(f2))     -   15) —NR^(h2)—C(═NR^(g2))NR^(e2)R^(f2),     -   16) —NR^(h2)—C(═N—OR^(g2))NR^(e2)R^(f2),     -   17) —NR^(i2)—C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   18) —NR^(i2)—C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   19) —C(═NR^(e2))R^(f2),     -   20) —C(═N—OR^(e2))R^(f2),     -   21) —C(═NR^(h2))—NR^(e2)R^(f2),     -   22) —C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   23) —C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   24) —NR^(e2)R^(f2),     -   25) —NR⁹²—NR^(e2)R^(f2),     -   26) —NR^(e2)OR^(f2),     -   27) —NR^(e2)—C(═O)R^(f2),     -   28) —C(═O)NR^(e2)R^(f2),     -   29) —C(═O)NR^(e2)OR^(f2),     -   30) —C(═O)NR^(g2)—NR^(e2)R^(f2),     -   31) —C(═O) R^(e2),     -   32) —C(═O)OR^(e2), and     -   33) —C(═N—OR^(h2))NR^(e2)R^(f2), and

each —R^(6b) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted),     -   4) a C₃₋₁₀ alicyclic group     -   (wherein the alicyclic group is optionally substituted),     -   5) —C(═NR^(e2))R^(e2),     -   6) —C(═N—OR^(e2))R^(f2),     -   7) —SO₂—NR^(e2)R^(f2),     -   8) —C(═NRha)—NR^(e2)R^(f2),     -   9) —C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   10) —C(═N—OR^(h2))NR^(g2)—NR⁶²R^(f2),     -   11) —C(═O)NR^(e2)R^(f2),     -   12) —C(═O)NR^(e2)OR^(f2),     -   13) —C(═O)NR^(g2)—NR^(e2)R^(f2),     -   14) —C(═O) R^(e2), and     -   15) —C(═N—OR^(h2))NR^(e2)R^(f2).

[Item A25]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A24, wherein R¹ and R² are the same or different, each independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a halogen atom,     -   3) a C₁₋₆ alkyl group,     -   4) a C₁₋₆ alkoxy group, and     -   5) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 3) to 5) is optionally         substituted).

[Item A26]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A25, wherein R¹ and R² are the same or different, each independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a halogen atom, and     -   3) an optionally substituted C₁₋₆ alkyl group.

[Item A27]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A26, wherein R¹ and R² are both hydrogen atoms.

[Item A28]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A27, wherein the compounds of formulas (1a) and (1b), the compounds of formulas (3a) and (3b), the compounds of formulas (4a) and (4b), or the compounds of formulas (5a) and (5b) are represented by formulas (6a) and (6b), respectively:

wherein

L³, L⁴, and R³ are defined the same as any one of items A1 to A24,

m is an integer 1, 2, or 3,

n is an integer 1, 2, or 3, and

m+n is 2, 3, or 4.

[Item A29]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A28, wherein m is 1 or 2, n is 1 or 2, and m+n is 2 or 3.

[Item A30]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A29, wherein m is 1 and n is 1.

[Item A31]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A30, wherein R⁵ is 5- or 6-membered aryl or heteroaryl selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(6a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) halogen,     -   4) a C₁₋₆ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e2)R^(f2), —C(═O)OR^(f2), or a hydroxyl group),     -   5) a C₁₋₄ alkoxy group     -   6) —NR^(e2)R^(f2), and     -   7) —C(═O)OR^(e2), and

each R^(6b) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group, and     -   3) a C₁₋₄ alkyl group,     -   (wherein the alkyl group is optionally substituted with         NR^(e2)R^(f2), —C(═O)OR^(f2), or a hydroxyl group).

[Item A32]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A31, wherein R^(e2), and R^(f2) are the same or different, each independently a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted C₃₋₁₀ alicyclic group.

[Item A33]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A32, wherein R^(e2) and R^(f2) are the same or different, each independently a hydrogen atom or an optionally substituted C₁₋₆ alkyl group.

[Item A34]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A33, wherein R^(e2) and R^(f2) are hydrogen atoms.

[Item A35]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A24 to A33, wherein R^(6a) is —NR^(e2)R^(f2), and one of R^(e2) and R^(f2) is a hydrogen atom and the other is a C₁₋₄ alkyl group (wherein the alkyl group is optionally substituted with an amino group or a hydroxyl group).

[Item A36]

The compound or the pharmaceutically acceptable salt thereof of item A1, represented by the following compound name or structural formula:

7-[(1-acetylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-acetylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-benzoylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-benzoylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{([1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[44.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxlic acid

7-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(phenylacetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(phenylacetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-phenylalanylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-phenylalanylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

2-hydroxy-7-[(1-D-tyrosylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-tyrosylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-D-histidylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-D-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

2-hydroxy-7-[(1-D-valylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-valylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-L-histidylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-L-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

7-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-prolylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-L-prolylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-L-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

[Item A37]

A salt of the compound of item A36, represented by the following compound name or structural formula:

8-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4-4.0)deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-[(1-benzoylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-{[1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9˜triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-{[1-(phenylacetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-[(1-D-phenylalanylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-[(1-D-tyrosylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-[(1-D-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-[(1-D-valylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-[(1-L-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-[(1-D-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

4,4-dihydroxy-8-[(1-L-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

8-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

[Item A38]

A compound represented by formula (11):

or a pharmaceutically acceptable salt thereof, wherein

R^(G) is a hydroxyl group, a thiol group, or —NHR^(a1), R^(a1), Z, L¹, L², X, R¹, R², R³, and R⁴ are defined the same as the definition according to item A1, and formula (1a) is defined the same as item A1.

[Item A39]

The compound or the pharmaceutically acceptable salt thereof according to item A38, wherein the compound of formula (11) is represented by formula (12):

wherein X, R¹, R², R³, and R⁴ are defined by the same the definition according to item A8.

[Item A40]

The compound or the pharmaceutically acceptable salt thereof according to item A38 or A39, wherein the compound of formula (12) is represented by formula (13):

wherein X, Y, ring A, L³, L⁴, R¹, R², R⁴, and R⁵ are defined the same as the definition according to any one of items A10 to A14 and items A16 to A27.

[Item A41]

The compound or the pharmaceutically acceptable salt thereof according to item A40, wherein X and R^(G) are hydroxyl groups, R⁴ is a carboxyl group, and ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.

[Item A42]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A38 to A41, wherein the compound of formula (13) is represented by formula (14):

wherein X, L³, L⁴, m, n, and R⁵ are defined the same as the definition according to item A28.

[Item A43]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A38 to A42, wherein R^(G) is a hydroxyl group or a thiol group.

[Item A44]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A38 to A43, wherein R^(G) is a hydroxyl group.

[Item A45]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A38 to A44, wherein X is a hydroxyl group or a C₁₋₆ alkoxy group.

[Item A46]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A38 to A45, wherein X is a hydroxyl group.

[Item A47]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A42 to A46, wherein m is 1 or 2, n is 1 or 2, and m+n is 2 or 3.

[Item A48]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A42 to A47, wherein m is 1, and n is 1.

[Item A49]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A38 to A48, wherein L³ is defined the same as the definition according to item A16 or A17.

[Item A50]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A38 to A49, wherein L⁴ is defined the same as the definition according to any one of items A18 to A20.

[Item A51]

The compound or the pharmaceutically acceptable salt thereof according to item A38, selected from the group consisting of the following compounds:

6-[(1-acetylazetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(methanesulfonyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-[(1-benzoylazetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{([1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(phenylacetyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-phenylalanylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-tyrosylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-6-[(1-D-histidylazetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-valylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-6-[(1-L-histidylazetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-prolylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-L-prolylazetidin-3-yl)oxy]benzoic acid

6-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}benzoic acid

[Item A52]

A medicament comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A51.

[Item A53]

The medicament according to item A52, which is a therapeutic drug or a prophylactic drug for a bacterial infection.

[Item A54]

A β-lactamase inhibiting agent comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A51 as an active ingredient.

[Item A55]

A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A51 and a pharmaceutically acceptable carrier.

[Item A56]

The pharmaceutical composition according to item A55, further comprising an additional agent.

[Item A57]

The pharmaceutical composition according to item A56, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.

[Item A58]

The pharmaceutical composition according to item A56 or A57, wherein the additional agent is a β-lactam agent.

[Item A59]

The pharmaceutical composition according to item A57 or A58, wherein a β-lactam agent, which is the additional agent, is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.

[Item A60]

The pharmaceutical composition according to item A58 or A59, wherein the β-lactam agent is selected from ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipenem.

[Item A61]

The pharmaceutical composition according to item A58 or A59, wherein the β-lactam agent is selected from aztreonam, tigemonam, BAL30072, SYN2416, or carumonam.

[Item A62]

The pharmaceutical composition according to item A55, characterized in that an additional agent is concomitantly administered.

[Item A63]

The pharmaceutical composition according to item A62, wherein the additional agent is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

[Item A64]

The pharmaceutical composition according to item A62 or A63, wherein the additional agent is a β-lactam agent.

[Item A65]

The pharmaceutical composition according to item A63 or A64, wherein a D-lactam agent, which is the additional agent, is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.

[Item A66]

The pharmaceutical composition according to item A64 or A65, wherein the n-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.

[Item A67]

The pharmaceutical composition according to item A64 or A65, wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam.

[Item A68]

The compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A51 for treating a bacterial infection.

[Item A69]

The compound or the pharmaceutically acceptable salt thereof according to item A68, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.

[Item A70]

The compound or the pharmaceutically acceptable salt thereof according to item A68 or A69, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.

[Item A71]

A medicament comprised of a combination of the compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A51 and at least one agent selected from the group consisting of therapeutic agents for sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, and an odontogenic infection.

[Item A72]

A pharmaceutical composition comprising a β-lactam agent, wherein the pharmaceutical composition is administered with the compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A51.

[Item A73]

A method for treating a bacterial infection, characterized in that a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to any one of items A1 to A51 is administered to a patient in need thereof.

[Item A74]

The method according to item A73, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.

[Item A75]

The method according to item A73 or A74, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.

[Item A76]

The method according to any one of items A73 to A75, characterized in that an additional agent is concomitantly administered.

The present invention also provides the following.

[Item 1]

A compound represented by formula (1a) or (1b):

or a pharmaceutically acceptable salt thereof, wherein

G is an oxygen atom, a sulfur atom, or —NR^(a1)—,

X is a hydroxyl group, an optionally substituted C₁₋₆ alkoxy group, or —NR^(a2)R^(b1),

R^(a1), R^(a2), and R^(b1) are the same or different, each independently

-   -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl     -   5) 5- or 6-membered heteroaryl,     -   6) a 4- to 10-membered non-aryl heterocycle,     -   7) a C₁₋₆ alkylcarbonyl group,     -   8) a C₃₋₁₀ alicyclic carbonyl group,     -   9) a C₆₋₁₀ arylcarbonyl group,     -   10) a 5- or 6-membered heteroarylcarbonyl group,     -   11) a C₁₋₆ alkylsulfonyl group,     -   12) a C₃₋₁₀ alicyclic sulfonyl group,     -   13) a C₆₋₁₀ arylsulfonyl group,     -   14) a 5- or 6-membered heteroarylsulfonyl group, or     -   15) —OR^(c1),     -   (wherein each substituent from 2) to 14) is optionally         substituted),

wherein R^(a2) and R^(b1) together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle,

R^(c1) is

-   -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl, or     -   6) a 4- to 10-membered non-aryl heterocycle,     -   (wherein each substituent from 2) to 6) is optionally         substituted),

L¹ is a single bond, an oxygen atom, a sulfur atom, —SO—, —SO₂—, —NR^(d)—, —NR^(d)C(═O)—, or —NR^(d)SO₂—,

L² is a single bond or an optionally substituted C₁₋₆ alkylene group,

Z is

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) a carboxyl group,     -   5) a C₃₋₁₀ alicyclic group,     -   6) C₆₋₁₀ aryl,     -   7) 5- or 6-membered heteroaryl,     -   8) a 4- to 10-membered non-aryl heterocycle,     -   9) a C₁₋₆ alkoxy group,     -   10) a C₃₋₁₀ alicyclic oxy group,     -   11) a C₆₋₁₀ aryloxy group,     -   12) a 5- or 6-membered heteroaryloxy group,     -   13) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   14) a C₁₋₆ alkylthio group,     -   15) a C₃₋₁₀ alicyclic thio group,     -   16) a C₆₋₁₀ arylthio group,     -   17) a 5- or 6-membered heteroarylthio group,     -   18) a 4- to 10-membered non-aryl heterocyclyl thio group,     -   (wherein each substituent from 5) to 18) is optionally         substituted),     -   19) —SO₂—NR^(e1)R^(f1),     -   20) —NR^(e1)—C(═O) OR^(f1),     -   21) —NR^(g2)—C(═O)NR^(e1)R^(f2),     -   22) —NR^(e1)—C(═S)R^(f1),     -   23) —NR^(e1)—C(═S)OR^(f1),     -   24) —NR^(g1)—C(═S)NR^(e1)R^(f1),     -   25) —NR^(g1)—CR^(e1)(═NR^(f1)),     -   26) —NR^(g1)—CR^(e1)(═N—OR^(f1)),     -   27) —NR^(h1)—C(═NR^(g1))NR^(e1)R^(f1),     -   28) —NR^(h1)—C(═N—OR^(g1))NR^(e1)R^(f1),     -   29) —NR^(i1)—C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   30) —NR^(i1)—C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   31) —NR^(e1)—SO₂—R^(f1),     -   32) —NR^(g1)—SO₂—NR^(e1)R^(f1),     -   33) —C(═O)OR^(e1),     -   34) —C(═S)OR^(e1),     -   35) —C(═S)NR^(e1)R^(f1),     -   36) —C(═S)NR^(e1)OR^(f1),     -   37) —C(═S)NR^(g1)—NR^(e1)R^(f1),     -   38) —C(═NR^(e1))R^(f1),     -   39) —C(═N—OR^(e1))R^(f1),     -   40) —C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   41) —C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   42) —NR^(e1)R^(f1),     -   43) —NR^(g1)—NR^(e1)R^(f1),     -   44) —NR^(e1)OR^(f1),     -   45) —NR^(e1)—C(═O)R^(f1),     -   46) —C(═O)NR^(g1)R^(f1),     -   47) —C(═O)NR^(e1)OR^(f1),     -   48) —C(═O)NR^(g1)—NR^(e1)R^(f1),     -   49) —C(═O) R^(e1),     -   50) —C(═NR^(g1))NR^(e1)R^(f1), or     -   51) —C(═N—OR^(h1))NR^(e1)R^(f1),     -   one of R¹, R², and R³ is a group represented by formula (2):

-   -   wherein         -   Y is an oxygen atom, a sulfur atom, or —N^(R1)—,         -   ring A is an optionally substituted 4- to 20-membered             non-aryl heterocycle,         -   L³ is —C(═O)—, —S(═O)—, or —S(═O)₂—,

L⁴ is

-   -   1) a single bond,     -   2) a C₁₋₆ alkylene group,     -   3) a C₃₋₁₀ cycloalkylene group,     -   4) a C₆₋₁₀ arylene group,     -   5) a 5- or 6-membered heteroarylene group,     -   6) a 4- to 10-membered non-aryl heterocyclylene group, or     -   7) —C(═N—OR^(h1))—,     -   (wherein each substituent from 2) to 6) is optionally         substituted), and         -   R⁵ is     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) a 4- to 10-membered non-aryl heterocycle,     -   5) C₆₋₁₀ aryl,     -   6) 5- or 6-membered heteroaryl,     -   7) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 2) to 7) is optionally         substituted), or     -   8) —NR^(e1)OH,         -   the remaining two (without the structure of formula (2)             among R¹, R², and R³) are the same or different, each             independently a hydrogen atom, a halogen atom, an optionally             substituted C₃₋₆ alkyl group, an optionally substituted C₁₋₆             alkoxy group, an optionally substituted C₁₋₆ alkylthio             group, an optionally substituted 5- or 6-membered             heteroaryl, or —NR^(a3)R^(b2),         -   R^(d), R^(e1), R^(e2), R^(f1), R^(f2), R^(g1), R^(g2),             R^(h1), R^(h2), R^(i1), R^(i2), and R^(j) are the same or             different, each independently a hydrogen atom, an optionally             substituted C₁₋₆ alkyl group, an optionally substituted             C₃₋₁₀ alicyclic group, optionally substituted C₆₋₁₀ aryl,             optionally substituted 5- or 6-membered heteroaryl, or an             optionally substituted 4- to 10-membered non-aryl             heterocycle,         -   a combination of R^(e1) and R^(f1) or R^(e2) and R^(f2),             when attached to the same nitrogen atom, together may form             an optionally substituted 4- to 10-membered             nitrogen-containing non-aryl heterocycle,         -   R⁴ is     -   1) —C(═O)R⁸,     -   2) —SO₂-L⁶-R⁸,     -   (wherein R⁸ in 1) and 2) is —NR^(a5)R^(b4),         —NR^(a5)-L⁷-B(OR^(m1))₂, —OR^(m1), or an optionally substituted         C₁₋₆ alkyl group, and L⁶ is a single bond or —NR^(a6)—),     -   3) —NR^(a4)R^(b3),     -   4) —B(OR^(a1))₂,     -   5) —PO(OR^(m1))(OR^(m2)),     -   6) optionally substituted 5-membered heteroaryl,     -   7) an optionally substituted 5-membered non-aryl heterocycle, or     -   8) a bioisostere of one of 1) to 7),     -   (wherein the formulas of 2), 4), 5), and 6) include a carboxylic         acid isostere, and 8) may include them in duplicates),         -   R^(a3), R^(a4), R^(a5), R^(a6), R^(b2), R^(b3), and R^(b4)             are the same or different, each independently having the             same definition as R^(a1), R^(a2), and R^(b1), wherein a             combination of R^(a3) and R^(b2), R^(a4) and R^(b3), or             R^(a5) and R^(b4), when attached to the same nitrogen atom,             together may form an optionally substituted 4- to             10-membered nitrogen-containing non-aryl heterocycle,         -   R^(m1) is     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl, or     -   6) a 4- to 10-membered non-aryl heterocycle,     -   (wherein each substituent from 2) to 6) is optionally         substituted),         -   wherein if R^(m1) is attached to a boron atom via an oxygen             atom, two R^(m1), as C₂₋₄ alkylene, together with the boron             atom and two oxygen atoms, may form a 5- to 7-membered             non-aryl heterocycle (wherein an alkylene moiety is             optionally substituted in the non-aryl heterocycle),         -   R^(m2) is a hydrogen atom, an optionally substituted C₁₋₆             alkyl group, or an optionally substituted C₃₋₁₀ alicyclic             group, and         -   L⁷ is an optionally substituted C₁₋₃ alkylene group.

[Item 2]

The compound or the pharmaceutically acceptable salt thereof according to item 1, wherein

L¹ is a single bond, a sulfur atom, —NR^(d)C(═O)—, or —NR^(d)SO₂—,

L² is a single bond or an optionally substituted C₁₋₆ alkylene group, and

Z is

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl,     -   6) a 4- to 10-membered non-aryl heterocycle,     -   7) —C(═N—OR^(e2))R^(f1), or     -   8) —NR^(e1)R^(f1).

[Item 3]

The compound or the pharmaceutically acceptable salt thereof according to item 1 or 2, wherein

Z-L²-L¹ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted C₁₋₆ alkylthio group.

[Item 4]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein Z-L²-L¹ is a hydrogen atom.

[Item 5]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein G is an oxygen atom.

[Item 6]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein X is a hydroxyl group or an optionally substituted C₁₋₆ alkoxy group.

[Item 7]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein X is a hydroxyl group.

[Item 8]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compounds of formulas (1a) and (1b) are represented by formulas (3a) and (3b), respectively:

wherein X, R¹, R², and R³ are defined the same as any one of the preceding items, and

R⁴ is selected from the group consisting of

-   -   1) —COOR^(a1) (wherein R^(m1) is a hydrogen atom, a C₁₋₆ alkyl         group, a C₃₋₁₀ alicyclic group, C₆₋₁₀ aryl, 5- or 6-membered         heteroaryl, or a 4- to 10-membered non-aryl heterocycle, wherein         the C₁₋₆ alkyl group, the C₃₋₁₀ alicyclic group, the C₆₋₁₀ aryl,         the 5- or 6-membered heteroaryl, and the 4- to 10-membered         non-aryl heterocycle are each optionally substituted), and     -   2) a bioisostere of 1).

[Item 9]

The compound or the pharmaceutically acceptable salt thereof according to item 8, wherein R⁴ is

-   -   1) —COOH (i.e., a carboxyl group), or     -   2) a carboxylic acid isostere.

[Item 10]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compounds of formulas (1a) and (1b) or the compounds of formulas (3a) and (3b) are represented by formulas (4a) and (4b), respectively:

wherein X, R⁴, Y, ring A, L³, L⁴, and R⁵ are defined the same as any one of the preceding items, and

R¹ and R² are the same or different, each independently a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, or a C₁₋₆ alkoxy group (wherein the C₁₋₆ alkyl group and the C₁₋₆ alkoxy group are optionally substituted with 1 to 5 halogen atoms).

[Item 11]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein ring A is an optionally substituted 4- to 10-membered non-aryl heterocycle.

[Item 12]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein ring A is an optionally substituted 4- to 7-membered non-aryl heterocycle.

[Item 13]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein Y is an oxygen atom or a sulfur atom.

[Item 14]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein Y is an oxygen atom.

[Item 15]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compounds of formulas (1a) and (1b), the compounds of formulas (3a) and (3b), or the compounds of formulas (4a) and (4b) are represented by formulas (5a) and (5b), respectively:

wherein ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.

[Item 16]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L³ is —C(═O)— or —S(═O)₂—.

[Item 17]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L³ is —C(═O)—.

[Item 18]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is a single bond, —C(═N—OR^(h1))—, or an optionally substituted C₁₋₆ alkylene group, wherein R^(h1) is an optionally substituted C₁₋₆ alkyl group.

[Item 19]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R¹ and R² are the same or different, each independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a halogen atom,     -   3) a C₁₋₆ alkyl group,     -   4) a C₁₋₆ alkoxy group, and     -   5) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 3) to 5) is optionally         substituted).

[Item 20]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R¹ and R² are the same or different, each independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a halogen atom, and     -   3) an optionally substituted C₁₋₆ alkyl group.

[Item 21]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R¹ and R² are both hydrogen atoms.

[Item 22]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compounds of formulas (1a) and (1b), the compounds of formulas (3a) and (3b), the compounds of formulas (4a) and (4b), or the compounds of formulas (5a) and (5b) are represented by formulas (6a) and (6b), respectively:

wherein L³, L⁴, and R⁵ are defined the same as any one of the preceding items,

-   -   m is an integer 1, 2, or 3,     -   n is an integer 1, 2, or 3, and     -   m+n is 2, 3, or 4.

[Item 23]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein m is 1 or 2, n is 1 or 2, and m+n is 2 or 3.

[Item 24]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein m is 1 and n is 1.

[Item 25]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is a single bond, or a C₁₋₆ alkylene group optionally substituted with —NR²¹R²² or ═NOR²³, wherein R²¹, R²², and R²³ are each independently a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted 4- to 10-membered non-aryl heterocyclyl carbonyl group.

[Item 26]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is a single bond, —CH₂—, —CH(NH₂)—, or —CH(NH₂)—CH₂—, wherein if an amino group is present in L⁴, carbon that attaches to the amino group attaches to L³.

[Item 27]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is a single bond, —CH₂—, —CMe(NH₂)—, —CH(NHMe)—, —CD(NH₂)— (wherein D represents a heavy hydrogen atom), —CH(NH₂)—, or —CH₂CH₂—.

[Item 28]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is a single bond, —CH₂—, or —CH(NH₂)—.

[Item 29]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R⁵ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted 4- to 10-membered non-aryl heterocycle, optionally substituted C₆₋₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, an optionally substituted C₁₋₆ alkylthio group, or —NR^(e1)OH, wherein R^(e1) is a hydrogen atom or an optionally substituted C₁₋₅ alkyl group.

[Item 30]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R⁵ is optionally substituted 5- or 6-membered heteroaryl or optionally substituted C₆₋₁₀ aryl.

[Item 31]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R⁵ is optionally substituted 5- or 6-membered heteroaryl.

[Item 32]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R⁵ is an optionally substituted 4- to 10-membered non-aryl heterocycle.

[Item 33]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is a single bond, and R⁵ is —NR^(e1)OH, wherein R^(a1) is a hydrogen atom or an optionally substituted C₁₋₆ alkyl group.

[Item 34]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is

-   -   1) —(CH₂)_(p)—CR¹⁰(NHR¹¹)—,     -   2) —(CH₂)_(q)—CR¹²R¹³—, or     -   3) —(CH₂)_(p)—CR¹⁰(NHR¹¹)—(CH₂)_(q)—CR¹²R¹³— (wherein p and q         are independently 0 or 1),

R¹⁰ is

-   -   1) a hydrogen atom,     -   2) a carboxyl group, or     -   3) —C(═O)NR^(10a)R^(10b),

R¹¹ is

-   -   1) a hydrogen atom,     -   2) —C(═O)R^(11a), or     -   3) an optionally substituted 5- or 6-membered non-aryl         heterocyclyl carbonyl group,     -   wherein if R¹⁰ is —C(═O)NR^(10a)R^(10b), R^(10b) and R¹¹         together may form —CH₂CH₂—,

R¹² is

-   -   1) a hydrogen atom, or     -   2) an optionally substituted C₃₋₄ alkyl group,

R¹³ is

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) an optionally substituted C₁₋₄ alkyl group,     -   4) a sulfanyl group,     -   5) a carboxyl group,     -   6) an optionally substituted C₁₋₄ alkylthio group,     -   7) —NR^(13a)R^(13b),     -   8) —NR^(13a)—C(═O)R^(13b),     -   9) an optionally substituted 5- or 6-membered non-aryl         heterocyclyl carbonylamino group,     -   10) —NR^(13a)—C(═O)NR^(13b)R^(13c),     -   11) —C(═O)NR^(13a)R^(13b),     -   12) —C(═O)NR^(13a)OR^(13b),     -   13) —S(═O)₂—R^(13a),     -   14) —S(═O)₂—NR^(13a)R^(13b),     -   15) —C(═O)NR^(13a)—S(═O)₂—R^(13b), or     -   16) —C(═O)NR^(13a)—S(═O)₂—NR^(13b)R^(13c), and

R^(10a), R^(10b), R^(11a), R^(13a), R^(13b), and R^(13c) are each independently a hydrogen atom or an optionally substituted C₁₋₄ alkyl group.

[Item 35]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein R⁵ is a hydrogen atom or an optionally substituted C₁₋₄ alkyl group.

[Item 36]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 31, wherein

R⁵ is selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(6a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) a nitro group,     -   5) halogen,     -   6) a C₁₋₄ alkyl group,     -   7) a C₃₋₁₀ alicyclic group,     -   8) a C₁₋₄ alkoxy group,     -   9) a C₃₋₁₀ alicyclic oxy group,     -   10) a C₆₋₁₀ aryloxy group,     -   11) a 5- or 6-membered heteroaryloxy group,     -   12) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   (wherein each substituent from 6) to 12) is optionally         substituted),     -   13) —SO₂—NR^(e2)R^(f2),     -   14) —NR^(g2)—CR^(e2)(═NR^(f2)),     -   15) —NR^(g2)—CR^(e2)(═N—OR^(f2)),     -   16) —NR^(h2)—C(═NR^(g2))NR^(e2)R^(f2),     -   17) —NR^(h2)—C(═N—OR^(g2))NR^(e2)R^(f2),     -   18) —NR^(i2)—C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   19) —NR^(i2)—C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   20) —C(═NR^(e2))R^(f2),     -   21) —C(═N—OR^(e2))R^(f2),     -   22) —C(═NR^(h2))—NR^(e2)R^(f2),     -   23) —C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   24) —C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   25) —NR^(e2)R^(f2),     -   26) —NR^(g2)—NR^(e2)R^(f2),     -   27) —NR^(e2)OR^(f2),     -   28) —NR^(e2)—C(═O)R^(f2),     -   29) —C(═O)NR^(e2)R^(f2),     -   30) —C(═O)NR^(e2)OR^(f2),     -   31) —C(═O)NR^(g2)—NR^(e2)R^(f2),     -   32) —C(═O)R^(e2),     -   33) —C(═O)OR², and     -   34) —C(═N—OR^(h2))NR^(e2)R^(f2), and

each R^(6b) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted)     -   4) a C₃₋₁₀ alicyclic group     -   (wherein the alicyclic group is optionally substituted),     -   5) —C(═NR^(e2))R^(f2),     -   6) —C(═N—OR^(e2))R^(f2),     -   7) —SO₂—NR^(e2)R^(f2),     -   8) —C(═NR^(h2))—NR^(e2)R^(f2),     -   9) —C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   10) —C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   11) —C(═O)NR^(e2)R^(f2),     -   12) —C(═O)NR^(e2)OR^(f2),     -   13) —C(═O)NR^(g2)—NR^(e2)R^(f2),     -   14) —C(═O) R^(e2), and     -   15) —C(═N—OR^(h2))NR^(e2)R^(f2).

[Item 37]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 31 and 36, wherein R⁵ is 5- or 6-membered aryl or heteroaryl selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(6a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) halogen,     -   4) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e2)R^(f2), a 5- or 6-membered non-aryl heterocycle,         —C(═O)OR^(f2), or a hydroxyl group),     -   5) a C₁₋₄ alkoxy group     -   6) —NR^(e2)R^(f2), and     -   7) —C(═O) OR^(e2), and

each R^(6b) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group, and     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e2)R^(f2), —C(═O)NR^(e2)R^(f2), —C(═O) OR^(f2), or a         hydroxyl group).

[Item 38]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 31, 36, and 37, wherein R^(e2) and R^(f2) are the same or different, each independently a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted C₃₋₁₀ alicyclic group.

[Item 39]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 31 and 36 to 38, wherein R^(e2) and R^(f2) are the same or different, each independently a hydrogen atom or an optionally substituted C₁₋₆ alkyl group.

[Item 40]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 31 and 36 to 39, wherein R^(e2) and R^(f2) are hydrogen atoms.

[Item 41]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 36 to 39, wherein R^(6a) is —NR^(e2)R^(f2), and one of R^(e2) and R^(f2) is a hydrogen atom and the other is a C₁₋₄ alkyl group (wherein the alkyl group is optionally substituted with an amino group or a hydroxyl group).

[Item 42]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 29 and 32, wherein R⁵ is a 4- to 6-membered non-aryl heterocycle selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(7a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) halogen,     -   5) a C₁₋₄ alkyl group,     -   6) a C₃₋₁₀ alicyclic group,     -   7) a C₁₋₄ alkoxy group,     -   8) a C₃₋₁₀ alicyclic oxy group,     -   9) a C₆₋₁₀ aryloxy group,     -   10) a 5- or 6-membered heteroaryloxy group,     -   11) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   (wherein each substituent from 5) to 11) is optionally         substituted),     -   12) —SO₂—NR^(e3)R^(f3),     -   13) —NR^(g2)—CR^(e3)(═NR^(f3))     -   14) —NR^(g2)—CR^(e3) (═N—OR^(f3)),     -   15) —NR^(h2)—C(═NR^(g2))NR^(e3)R^(f3),     -   16) —NR^(h2)—C(N—OR^(g2))NR^(e3)R^(f3),     -   17) —NR^(i2)—C(═NR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   18) —NR^(i2)—C(═N—OR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   19) —C(═NR^(e3))R^(f3),     -   20) —C(═N—OR^(e3))R^(f3),     -   21) —C(═NR^(h2))—NR^(e3)R^(f3),     -   22) —C(═NR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   23) —C(═N—OR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   24) —NR^(e3)R^(f3),     -   25) —NR^(g2)—NR^(e3)R^(f3),     -   26) —NR^(e3)OR^(f3),     -   27) —NR^(e3)—C(═O)R^(f3),     -   28) —C(═O)NR^(e3)R^(f3),     -   29) —C(═O)NR^(e3)OR^(f3),     -   30) —C(═O)NR^(g2)—NR^(e3)R^(f3),     -   31) —C(═O)R^(e3),     -   32) —C(═O)OR^(e3), and     -   33) —C(═N—OR^(h2))NR^(e3)R^(f3),

each R^(7b) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a C₃₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted),     -   4) a C₃₋₁₀ alicyclic group     -   (wherein the alicyclic group is optionally substituted),     -   5) —C(═NR^(e3))R^(f3),     -   6) —C(═N—OR^(e3))R^(f3),     -   7) —SO₂—NR^(e3)R^(f3),     -   8) —C(═NR^(h2))—NR^(e3)R^(f3),     -   9) —C(═NR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   10) —C(═N—OR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   11) —C(═O)NR^(e3)R^(f3),     -   12) —C(═O)NR^(e3)R^(f3),     -   13) —C(═O)NR^(g2)—NR^(e3)R^(f3),     -   14) —C(═O) R^(e3), and     -   15) —C(═N—OR^(h2))NR^(e3)R^(f3), and

R^(e3) and R^(f3) are defined the same as R^(e2) and R^(f2) according to item 1.

[Item 43]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 29, 32, and 42, wherein

R⁵ is a 4- to 6-membered non-aryl heterocycle selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(7a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) halogen,     -   4) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e3)R^(f3), a 5- or 6-membered non-aryl heterocycle,         —C(═O)OR^(f3), or a hydroxyl group),     -   5) a C₁₋₄ alkoxy group     -   6) —NR^(e3)R^(f3),     -   7) —C(═O)OR^(e3),     -   8) C₆₋₁₀ aryl, and     -   9) —C(═O)NR^(e3)R^(f3),

each R^(7b) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group, and     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e3)R^(f3), —C(═O)OR^(f3), or a hydroxyl group), and

R^(e3) and R^(f3) are defined the same as R^(e2) and R^(f2) according to any one of items 38 to 40.

[Item 44]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein

L⁴ is —CH(NH₂)—CHR¹³—, wherein carbon that attaches to the NH₂ attaches to L³,

R⁵ is a hydrogen atom, and

R¹³ is

-   -   1) —NH—C(═O)CH₃,     -   2) —NH—C(═O)NH₂,     -   3) —NH—C(═O)CH(NH₂)—CH₂C(═O)NH₂,     -   4) —NH—C(═O)CH₂—NH₂,     -   5) —NH—C(═O)CH(NH₂)—CH₂OH, or     -   6) a pyrrolidin-2-ylcarbonylamino group.

[Item 45]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L⁴ is —CH(NH₂)—CR¹²R¹³—, wherein carbon that attaches to the NH₂ attaches to L³,

-   -   R⁵ is a hydrogen atom or methyl,     -   R¹² is a hydrogen atom or methyl, and     -   R¹³ is a benzylthio group or a sulfanyl group.

[Item 46]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein L is —CH(NH₂)—(CH₂)_(q)—CHR¹³—, wherein q is 0 or 1, and carbon that attaches to the NH₂ attaches to L³,

R⁵ is a hydrogen atom, and

R¹³ is

-   -   1) a carboxyl group,     -   2) —C(═O)NH₂,     -   3) —C(═O)NH(CHO),     -   4) —C(═O)N(CH₃)₂,     -   5) —C(═O)NH—(CH₂)₂—OH,     -   6) —C(═O)NH—(CH₂)₂—NH₂,     -   7) —C(═O)NH—S(═O)₂—CH₃,     -   8) —C(═O)NHOH,     -   9) —S(═O)₂—NH₂,     -   10) —S(═O)₂—CH₃, or     -   11) a hydroxyl group.

[Item 47]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein

L⁴ is —CH(NHR¹¹)—CH₂—, wherein carbon that attaches to the NHR¹¹ attaches to L³,

R⁵ is hydrogen, and

R¹¹ is

-   -   1) —C(═O)CH(NH₂)—CH₂C(═O)NH₂,     -   2) —C(═O)CH₂—NH₂,     -   3) —C(═O)CH(CH₃)—NH₂,     -   4) —C(═O)CH(NH₂)—CH₂OH, or     -   5) pyrrolidin-2-ylcarbonyl.

[Item 48]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein

L⁴ is —CH(NHR¹¹)—CH(COOH)—, wherein carbon that attaches to the NHR¹¹ attaches to L³,

R⁵ is hydrogen, and

R¹¹ is

-   -   1) —C(═O)CH(NH₂)—CH₂C(═O)NH₂,     -   2) —C(═O)CH₂—NH₂,     -   3) —C(═O)CH(CH₃)—NH₂,     -   4) —C(═O)CH(NH₂)—CH₂OH, or     -   5) pyrrolidin-2-ylcarbonyl.

[Item 49]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein

L⁴ is —CHR¹³— or —CH₂—CHR¹³—,

R⁵ is hydrogen, and

R¹³ is —C(═O)NH₂ or —C(═O)NHOH.

[Item 50]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein

L⁴ is —CH₂—CR¹⁰ (NH₂)—, wherein the CH₂ attaches to L³,

R⁵ is hydrogen, and

R¹⁰ is a carboxy group or —C(═O)NH₂.

[Item 51]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein

L⁴ is —(CH₂)_(p)—CR¹⁰(NHR¹¹)—(CH₂)_(q)—CHR¹³— or —CHR¹³—(CH₂)_(q)—CR¹⁰(NHR²¹)—(CH₂)_(p)—, wherein q is 0 or 1,

R⁵ is hydrogen,

-   -   (1) if L⁴ is —CHR¹³—(CH₂)_(q)—CR¹⁰ (NHR¹¹)—(CH₂)_(p)—,     -   carbon of the —CHR³— group attaches to L³,

p is 0,

R¹⁰ is a hydrogen atom, a carboxyl group, or —C(═O)NHR^(10b),

R¹¹ is a hydrogen atom,

R^(10b) is a hydrogen atom,

-   -   wherein if R¹⁰ is —C(═O)NHR^(10b), R^(10b) and R¹¹ together may         form —CH₂CH₂—, and

R¹³ is a hydrogen atom, and

-   -   (2) if L⁴ is —(CH₂)_(p)—CR¹⁰ (NHR¹¹)—(CH₂)_(q)—CHR¹³—,     -   carbon of the —(CH₂)_(p)— group attaches to L³,

p is 1,

R¹⁰ and R¹¹ are both hydrogen atoms,

R¹³ is a carboxyl group or —C(═O)NR^(13a)R^(13b), and

R^(13a) and R^(13b) are each independently a hydrogen atom or an optionally substituted C₁₋₄ alkyl group.

[Item 52]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein

L⁴ is —CR¹²(NH₂)—,

R¹² is a hydrogen atom or a methyl group, and

R⁵ is a C₁₋₄ alkyl group optionally substituted with a hydroxyl group.

[Item 53]

The compound or the pharmaceutically acceptable salt thereof according to item 1, represented by the following compound name or structural formula:

7-[(1-acetylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-acetylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-imidazol-S-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carbolic acid

2-hydroxy-7-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{([1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-benzoylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-benzoylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic

4,4-dihydroxy-8-({1-([4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-([1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino (1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(phenylacetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(phenylacetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic

4,4-dihydroxy-8-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-phenylalanylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-phenylalanylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-tyrosylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-tyrosylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-D-histidylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-D-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-valylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-valylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-L-histidylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-L-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-prolylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-L-prolylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-L-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

[Item 54]

The compound or the pharmaceutically acceptable salt thereof of item 1, represented by the following compound name or structural formula:

7-({1-[(2R)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2R)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{1-[(2S)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2S)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(1-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(1-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({[1-(4H-1,2,4-triazole-3-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(4H-1,2,4-triazole-3-sulfonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[2-amino-2-(1H-imidazol-4-yl)(²H) ethanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[2-amino-2-(1H-imidazol-4-yl)(²H) ethanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[2-amino-2-(1H-imidazol-4-yl)propanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[2-amino-2-(1H-imidazol-4-yl)propanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({(3S)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({(3S)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(4-hydroxy-6-methylpyridine-3-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(4-hydroxy-6-methylpyridine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

7-({1-[amino(1-methyl-1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino (1-methyl-1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{amino[1-(carboxymethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{amino[1-(carboxymethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{amino[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{amino[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic

8-({1-[amino(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{1-[amino (1-methyl-1H-pyrazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(1-methyl-1H-pyrazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({(3R)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({(3R)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({-[amino(2-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino (2-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic

8-({1-[amino(1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(1H-imidazole-4-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1H-imidazole-4-sulfonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{(1-(pyridine-3-sulfonyl)azetidin-3-yl)oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(pyridine-3-sulfonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(1-oxo-1λ⁵-pyridine-2-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1-oxo-1λ⁵-pyridine-2-sulfonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2-amino-1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2-amino-1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(2-amino-1,3-thiazole-4-carbonyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(2-amino-1,3-thiazole-4-carbonyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{[1-(2-aminoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{[1-(2-aminoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(1H-imidazole-4-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1H-imidazole-4-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(1H-imidazole-2-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1H-imidazole-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-({4-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-({4-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-({4-[(piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-({4-[(piperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-{[4-(2-hydroxyethyl)-1H-1, 2, 3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-{[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-{[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-{[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-({5-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-({5-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{[4-(carboxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{[4-(carboxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{[1-(carboxymethyl)-1H-1,2,3-triazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-([1-(carboxymethyl)-1H-1,2,3-triazol-4-yl]acetyl)azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

7-({1-[amino (1H-1, 2, 3-triazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino (3,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(3,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(2,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(2,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(S-benzyl-D-cysteinyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(S-benzyl-D-cysteinyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-D-cysteinylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

7-[(1-D-cysteinylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

2-hydroxy-7-{[1-(3-sulfanyl-D-valyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(3-sulfanyl-D-valyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2S)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2S)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(D-alanyl-D-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(D-alanyl-D-alanyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-L-asparaginylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-L-asparaginylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

7-[(1-D-asparaginylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-D-asparaginylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2R)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2R)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-serylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-serylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(4-amino-4-oxobutanoyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(4-amino-4-oxobutanoyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-D-glutaminylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-D-glutaminylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[3-(carbamoylamino)-D-alanyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[3-(carbamoylamino)-D-alanyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(3-acetamido-D-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-([1-(3-acetamido-D-alanyl)azetidin-3-yl]oxy-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(N,N-dimethyl-D-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(N,N-dimethyl-D-asparaginyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(N-methyl-D-asparaginyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(N-methyl-D-asparaginyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-L-serylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborine-8-carboxylic acid

4,4-dihydroxy-8-[(1-L-serylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

2-hydroxy-7-{[1-(4-hydroxyprolyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(4-hydroxyprolyl)azetidin-3-yl]oxy}-S-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(4R)-4-(trifluoromethyl)-D-prolyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(4R)-4-(trifluoromethyl)-D-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

7-({1-[(4S)-4-fluoro-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(4S)-4-fluoro-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{[(3R,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{[(3R,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-([(3S,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl)azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{[(3S,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-[(1-{[(2R,4S)-4-fluoropyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-[(1-{[(2R,4S)-4-fluoropyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(4,4-difluoro-L-prolyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(4,4-difluoro-L-prolyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(4R)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(4R)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(pyrrolidine-3-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(pyrrolidine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(4S)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(4S)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-(6),7,9-triene-7-carboxylic acid

7-({1-[(4S)-4-amino-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(4S)-4-amino-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(4S)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(4S)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(3R)-3-hydroxy-L-prolyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(3R)-3-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(4,4-dimethyl-L-prolyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{([1-(4,4-dimethyl-L-prolyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(pyrrolidin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(pyrrolidin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(piperidine-2-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(piperidine-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxlic acid

2-hydroxy-7-{[1-(piperidine-3-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(piperidine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(piperidine-4-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(piperidine-4-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(2S)-oxolane-2-carbonyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(2S)-oxolane-2-carbonyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(4R)-4-phenyl-L-prolyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(4R)-4-phenyl-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

2-hydroxy-7-{[1-(1-methyl-L-prolyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(1-methyl-L-prolyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(piperidin-3-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(piperidin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(morpholin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(morpholin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(azetidin-3-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(azetidin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[3-(pyrrolidin-2-yl)propanoyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[3-(pyrrolidin-2-yl)propanoyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(4R)-4-amino-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(4R)-4-amino-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(4R)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(4R)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[amino(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[amino(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(piperidin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(piperidin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(4S)-4-carbamoyl-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(4S)-4-carbamoyl-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-{[(3R)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborine-8-carboxylic acid

4,4-dihydroxy-8-[(1-{[(3R)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-{[(3S)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborine-8-carboxylic acid

4,4-dihydroxy-[(1-{([(3S)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-{[(2R)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborine-8-carboxylic acid

4,4-dihydroxy-8-[(1-{([(2R)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-{[(2S)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborine-8-carboxylic acid

4,4-dihydroxy-8-[(1-{[(2S)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(piperazin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{(1-[(piperazin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(1,1-dioxo-1λ⁶-thiomorpholin-2-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(1,1-dioxo-1λ⁶-thiomorpholin-2-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(2S)-4-acetamido-2-aminobutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(2S)-4-acetamido-2-aminobutanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(L-α-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(L-α-asparaginyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(L-alanyl-L-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(L-alanyl-L-alanyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(glycyl-D-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{([1-(glycyl-D-alanyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

N-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-α-asparagine

N-[(2R)-1-{3-[(7-carboxy-4,4-hydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-trien-8-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-α-asparagine

N¹-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-aspartamide

N¹-[(2R)-1-{3-[(7-carboxy-4,4-hydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-trien-8-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-aspartamide

N-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-serinamide

N-([2R)-1-{3-[(7-carboxy-4,4-hydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-trien-8-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-serinamide

7-({1-[(3S)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(3S)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(2-methyl-D-seryl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(2-methyl-D-seryl)azetidin-3-yl]oxy}-S-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-{[1-(2-methyl-L-seryl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-{[1-(2-methyl-L-seryl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-({1-[(3-oxopiperazin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-({1-[(3-oxopiperazin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(3S)-3-amino-5-carboxypentanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(3S)-3-amino-5-carboxypentanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(3R)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(3R)-3-amino-3-carboxypropanoyl]azetidin-3-yl)oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(4R)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(3R)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(3S)-3,6-diamino-6-oxohexanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(3S)-3,6-diamino-6-oxohexanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(D-α-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(D-α-asparaginyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(D-at-glutaminyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{[1-(D-α-glutaminyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-({1-[(4S)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-({1-[(4S)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

7-{[1-(L-α-glutaminyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

8-{([1-(L-α-glutaminyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-D-threonylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-D-threonylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid

2-hydroxy-7-[(1-L-threonylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

4,4-dihydroxy-8-[(1-L-threonylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic

[Item 55]

A compound represented by formula (11):

or a pharmaceutically acceptable salt thereof, wherein R^(G) is a hydroxyl group, a thiol group, or —NHR^(a1), R^(a1), Z, L¹, L², X, R¹, R², R³, and R⁴ are defined the same as the definition according to item 1, and formula (1a) is defined the same as item 1.

[Item 56]

The compound or the pharmaceutically acceptable salt thereof according to item 55, wherein the compound of formula (11) is represented by formula (12):

wherein X, R¹, R², R³, and R⁴ are defined the same as the definition according to any one of the preceding items.

[Item 57]

The compound or the pharmaceutically acceptable salt thereof according to item 55 or 56, wherein the compound of formula (12) is represented by formula (13):

wherein X, Y, ring A, L³, L⁴, R¹, R², R⁴, and R⁵ are defined the same as the definition according to any one of the preceding items.

[Item 58]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 57, wherein X and R^(G) are hydroxyl groups, R⁴ is a carboxyl group, and ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.

[Item 59]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 58, wherein the compound of formula (13) is represented by formula (14):

wherein X, L³, L⁴, m, n, and R⁵ are defined the same as the definition according to any one of the preceding items.

[Item 60]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 59, wherein R^(G) is a hydroxyl group or a thiol group.

[Item 61]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 60, wherein R^(G) is a hydroxyl group.

[Item 62]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 61, wherein X is a hydroxyl group or a C₁₋₆ alkoxy group.

[Item 63]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 62, wherein X is a hydroxyl group.

[Item 64]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 63, wherein m is 1 or 2, n is 1 or 2, and m+n is 2 or 3.

[Item 65]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 64, wherein m is 1, and n is 1.

[Item 66]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 65, wherein L³ is defined the same as the definition according to any one of the preceding items.

[Item 67]

The compound or the pharmaceutically acceptable salt thereof according to any one of items 55 to 66, wherein L⁴ and R⁵ are defined the same as the definitions according to any one of the preceding items.

[Item 68]

The compound or the pharmaceutically acceptable salt thereof according to item 55, selected from the group consisting of the following compounds:

6-[(1-acetylazetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(methanesulfonyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-((methylsulfanyl)acetyl)azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-[(1-benzoylazetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{([1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(phenylacetyl) azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[((1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3H-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-phenylalanylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-tyrosylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-6-[(1-D-histidylazetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-valylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-6-[(1-L-histidylazetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-prolylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-L-prolylazetidin-3-yl)oxy]benzoic acid

6-(1-{[4 (2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-2-hydroxybenzoic acid

and

3-(2-boronoethyl)-2-hydroxy-6-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}benzoic acid

[Item 69]

The compound or the pharmaceutically acceptable salt thereof according to item 55, selected from the group consisting of the following compounds:

6-({1-[(2R)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(2S)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(1-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(4H-1,2,4-triazole-3-sulfonyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[2-amino-2-(1H-imidazol-4-yl)(²H)ethanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[2-amino-2-(1H-imidazol-4-yl)propanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({(3S)-1-amino(1H-imidazol-4-yl)acetyl)pyrrolidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(4-hydroxy-6-methylpyridine-3-carbonyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[amino(1-methyl-H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-[(1-{amino[1-(carboxymethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-[(1-{amino[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(1-methyl-1H-pyrazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({(3R)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(2-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(1H-imidazole-4-sulfonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(pyridine-3-sulfonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[(1-(1-oxo-1λ⁵-pyridine-2-sulfonyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[(2-amino-1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-{[1-(2-amino-1,3-thiazole-4-carbonyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-[(1-{[1-(2-aminoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(1H-imidazole-4-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(1H-imidazole-2-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-({4-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-({4-[(piperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-{[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-{[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-({5-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-6-[(1-{[4-(carboxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-[(1-{[1-(carboxymethyl)-1H-1,2,3-triazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxybenzoic

6-({1-[amino(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[amino(3,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(2,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-{[1-(S-benzyl-D-cysteinyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-[(1-D-cysteinylazetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(3-sulfanyl-D-valyl)azetidin-3-yl]oxy}benzoic acid

6-({1-[1(2S)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-{[1-(D-alanyl-D-alanyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-[(1-L-asparaginylazetidin-3-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-[(1-D-asparaginylazetidin-3b-yl)oxy]-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(2R)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-serylazetidin-3-yl)oxy]benzoic acid

6-{[1-(4-amino-4-oxobutanoyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-[(1-D-glutaminylazetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-({1-[3-(carbamoylamino)-D-alanyl]azetidin-3-yl}oxy)-2-hydroxybenzoic ac id

6-{[1-(3-acetamido-D-alanyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-{[1-(N,N-dimethyl-D-asparaginyl)azetidin-3-yl]oxy}-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(N-methyl-D-asparaginyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-L-serylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(4-hydroxyprolyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(4R)-4-(trifluoromethyl)-D-prolyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-6-({1-[(4S)-4-fluoro-L-prolyl]azetidin-3-yl}oxy)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({-[(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-6-[(1-{[(3R,5S)-5-(dimethylcarbamoyl) pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-[(1-{[(3S,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-[(1-{[(2R,4S)-4-fluoropyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-{(1-(4,4-difluoro-L-prolyl)azetidin-3-yl)oxy}-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(4R)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(pyrrolidine-3-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(4S)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[(4S)-4-amino-L-prolyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(4S)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(3R)-3-hydroxy-L-prolyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-6-([1-(4,4-dimethyl-L-prolyl)azetidin-3-yl]oxy)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(pyrrolidin-2-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(piperidine-2-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-([1-(piperidine-3-carbonyl)azetidin-3-yl]oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(piperidine-4-carbonyl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(2S)-oxolane-2-carbonyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(4R)-4-phenyl-L-prolyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{(1-(1-methyl-L-prolyl)azetidin-3-yl)oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(piperidin-3-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(morpholin-2-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[(azetidin-3-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[3-(pyrrolidin-2-yl)propanoyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[(4R)-4-amino-L-prolyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(4R)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[amino(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(piperidin-2-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-6-({1-[(4S)-4-carbamoyl-L-prolyl]azetidin-3-yl}-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[1-{[(3R)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-{([(3S)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-{[(2R)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-{[(2S)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(piperazin-2-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-6-({1-[(1,1-dioxo-1Δ⁶-thiomorpholin-2-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxybenzoic acid

6-({1-[(2S)-4-acetamido-2-aminobutanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-{[1-(L-α-asparaginyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-{[1-(L-alanyl-L-alanyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-{[1-(glycyl-D-alanyl)azetidin-3-yl]oxy}-2-hydroxybenzoic acid

N-[(2R)-1-{3-[4-(2-boronoethyl)-2-carboxy-3-hydroxyphenoxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-α-asparagine

N¹-[(2R)-1-{3-[4-(2-boronoethyl)-2-carboxy-3-hydroxyphenoxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-aspartamide

N-[(2R)-1-{3-[4-(2-boronoethyl)-2-carboxy-3-hydroxyphenoxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-serinamide

6-({1-[(3S)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)benzoic acid

3-(2-boronoethyl)-6-({1-[(dimethylamino)(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(2-methyl-D-seryl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-{[1-(2-methyl-L-seryl)azetidin-3-yl]oxy}benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-({1-[(3-oxopiperazin-2-yl)acetyl]azetidin-3-yl}oxy)benzoic acid

6-({1-[(3S)-3-amino-5-carboxypentanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(3R)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

6-({1-[(4R)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-({1-[(3S)-3,6-diamino-6-oxohexanoyl]azetidin-3-yl}oxy)-2-hydroxybenzoic acid

6-{[1-(D-α-asparaginyl)azetidin-3-yl]oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-{[1-(D-α-glutaminyl)azetidin-3-yl]oxy}-2-hydroxybenzoic acid

6-({1-[(4S)-4-amino-4-carboxybutanoyl]azetidin-3-yl)oxy}-3-(2-boronoethyl)-2-hydroxybenzoic acid

3-(2-boronoethyl)-6-{([1-(L-α-glutaminyl)azetidin-3-yl]oxy}-2-hydroxybenzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-D-threonylazetidin-3-yl)oxy]benzoic acid

3-(2-boronoethyl)-2-hydroxy-6-[(1-L-threonylazetidin-3-yl)oxy]benzoic acid

[Item 70]

A medicament comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 69.

[Item 71]

The medicament according to item 70, which is a therapeutic drug or a prophylactic drug for a bacterial infection.

[Item 72]

A β-lactamase inhibiting agent comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 69 as an active ingredient.

[Item 73]

A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of items 1 to 69 and a pharmaceutically acceptable carrier.

[Item 74]

The pharmaceutical composition according to item 73, further comprising an additional agent.

[Item 75]

The pharmaceutical composition according to item 74, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.

[Item 76]

The pharmaceutical composition according to item 74 or 75, wherein the additional agent is a β-lactam agent.

[Item 77]

The pharmaceutical composition according to item 75 or 76, wherein a β-lactam agent, which is the additional agent, is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.

[Item 78]

The pharmaceutical composition according to item 76 or 77, wherein the β-lactam agent is selected from ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipenem.

[Item 79]

The pharmaceutical composition according to item 76 or 77, wherein the β-lactam agent is selected from aztreonam, tigemonam, BAL30072, SYN2416, or carumonam.

[Item 80]

The pharmaceutical composition according to item 73, characterized in that an additional agent is concomitantly administered.

[Item 81]

The pharmaceutical composition according to item 80, wherein the additional agent is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

[Item 82]

The pharmaceutical composition according to item 80 or 81, wherein the additional agent is a (β-lactam agent.

[Item 83]

The pharmaceutical composition according to item 81 or 82, wherein a β-lactam agent, which is the additional agent, is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefeulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.

[Item 84]

The pharmaceutical composition according to item 82 or 83, wherein the D-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.

[Item 85]

The pharmaceutical composition according to item 82 or 83, wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam.

[Item 86]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items for treating a bacterial infection.

[Item 87]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.

[Item 88]

The compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.

[Item 89]

A medicament comprised of a combination of the compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items and at least one agent selected from the group consisting of therapeutic agents for sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, and an odontogenic infection.

[Item 90]

A pharmaceutical composition comprising a β-lactam agent, wherein the pharmaceutical composition is administered with the compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items.

[Item 91]

A method for treating a bacterial infection, characterized in that a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to any one of the preceding items is administered to a patient in need thereof.

[Item 92]

The method according to any one of the preceding items, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.

[Item 93]

The method according to any one of the preceding items, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.

[Item 94]

The method of any one of the preceding items, characterized in that an additional agent is concomitantly administered.

The present invention is intended so that one or more of the features described above can be provided not only as the explicitly disclosed combinations, but also as other combinations thereof. Additional embodiments and advantages of the invention are recognized by those skilled in the art by reading and understanding the following detailed description as needed.

Advantageous Effects of Invention

The compound of the invention has excellent inhibitory action against serine-β-lactamase with a serine residue at the center of enzymatic activity. A better embodiment of the compound of the invention is expected to have a broad β-lactamase inhibitory action or metallo-β-lactamase inhibitory action with zinc (Zn²⁺) at the center of enzymatic activity against multiple types of β-lactamases. Therefore, the compound of the invention is useful alone or in concomitant use with a β-lactam agent as a therapeutic agent and/or prophylactic agent for a bacterial infection in which a bacteria that can have a β-lactamase is involved, i.e., sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.

Description of Embodiments

The present invention is described hereinafter in more detail.

Throughout the entire specification, a singular expression should be understood as encompassing the concept thereof in the plural form, unless specifically noted otherwise. Thus, singular articles (e.g., “a”, “an”, “the”, and the like in the case of English) should also be understood as encompassing the concept thereof in the plural form, unless specifically noted otherwise. The terms used herein should also be understood as being used in the meaning that is commonly used in the art, unless specifically noted otherwise. Thus, unless defined otherwise, all terminologies and scientific technical terms that are used herein have the same meaning as the general understanding of those skilled in the art to which the present invention pertains. In case of a contradiction, the present specification (including the definitions) takes precedence.

The terms and the general technologies that are used herein are first described.

Unless specifically noted otherwise, the term “group” refers to a monovalent group. Examples of groups that are not a monovalent group include alkylene groups (divalent). The term “group” may also be omitted in the following descriptions of substituents or the like.

Unless specifically limited, the number of substituents when defined as “optionally substituted” or “substituted” is not particularly limited herein, as long as a substitution is possible. The number of substituents is one or multiple substituents. Moreover, unless indicated otherwise, the description for each substituent is also applicable when the substituent is a part of or a substituent of another group.

A substituent in “optionally substituted” is selected from substituent group α that consists of the following. The substitution is optionally substituted with 1 to 5 of the same or different substituents. While not particularly limited by the type of substituent, if an atom to which the substituent attaches is an oxygen atom, a nitrogen atom, or a sulfur atom, the substituent is limited to the following substituents that attaches to a carbon atom.

Substituent group α includes

-   -   1) a halogen atom     -   2) a hydroxyl group     -   3) a carboxyl group     -   4) a cyano group     -   5) a sulfanyl group,     -   6) a nitro group,     -   7) a C₁₋₆ alkyl group     -   8) a C₂₋₆ alkenyl group     -   9) a C₂₋₆ alkynyl group     -   10) a C₁₋₆ alkoxy group     -   11) a C₁₋₆ alkylthio group     -   12) a C₁₋₆ alkylcarbonyl group     -   13) a C₁₋₆ alkylsulfonyl group     -   (wherein each substituent from 7) to 13) is optionally         substituent with 1 to 5 of the same or different sub         substituents selected from substituent group β)     -   14) a C₃₋₁₀ alicyclic group     -   15) a C₃₋₁₀ alicyclic oxy group     -   16) a C₆₋₁₀ aryloxy group     -   17) a 5- or 6-membered heteroaryloxy group     -   18) a 4- to 10-membered non-aryl heterocyclyl oxy group     -   19) a C₃₋₁₀ alicyclic thio group     -   20) a C₆₋₁₀ arylthio group     -   21) a 5- or 6-membered heteroarylthio group     -   22) a 4- to 10-membered non-aryl heterocyclyl thio group     -   23) C₆₋₁₀ aryl     -   24) 5- or 6-membered heteroaryl     -   25) a 4- to 10-membered non-aryl heterocycle     -   26) a C₃₋₁₀ alicyclic carbonyl group     -   27) a C₆₋₁₀ arylcarbonyl group     -   28) a 5- or 6-membered heteroarylcarbonyl group     -   29) a 4- to 10-membered non-aryl heterocyclyl carbonyl group     -   30) a 4- to 10-membered non-aryl heterocyclyl carbonylamino         group     -   31) a C₃₋₁₀ alicyclic sulfonyl group     -   32) a C₆₋₁₀ arylsulfonyl group     -   33) a 5- or 6-membered heteroarylsulfonyl group     -   34) a 4- to 10-membered non-aryl heterocyclyl sulfonyl group     -   (wherein each substituent from 14) to 34) is optionally         substituted with 1 to 5 of substituent group β or 1) a C₁₋₆         alkyl group)     -   35) —NR^(10a)R^(11a)     -   36) —SO₂—R^(10b)     -   37) —SO₂—NR^(10b)R^(11b)     -   38) —NR^(10c)—C(═O)R^(11c)     -   39) —NR^(10d)—C(═O)OR^(11d)     -   40) —NR^(12a)—C(═O)NR^(10e)R^(11e)     -   41) —NR^(10f)—C(═S)R^(11f)     -   42) —NR^(10g)—C(═S)OR^(11g),     -   43) —NR^(12b)—C(═S)NR^(10h)R^(11h)     -   44) —NR^(10i)—SO₂—R^(11i)     -   45) —NR^(12c)—SO₂—NR^(10j)R^(11j)     -   46) —C(═O)OR^(10k)     -   47) —C(═O)NR^(10l)R^(11k)     -   48) —C(═O)NR^(10m)OR^(11l)     -   49) —C(═O)NR^(12d)—NR^(10n)R^(11m)     -   50) —C(═S)OR^(10o)     -   51) —C(═S)NR^(10p)R^(11n)     -   52) —C(═S)NR^(10q)OR^(11o)     -   53) —C(═S)NR^(12e)—NR^(10r)R^(11p)     -   54) —C(═NR^(13a))R^(10s)     -   55) —C(═NR^(23b))CHO     -   56) —C(═NR^(13c))NR^(10t)R^(11q)     -   57) —C(═NR^(13d))NR^(12f)—NR^(10u)R^(11r)     -   58) —NR^(17c)—C(═NR^(13k))R^(17d)     -   59) —NR^(12g)—C(═NR^(13e))—NR^(10v)R^(11a)     -   60) —NR¹⁴—C(═NR^(13f))—NR^(12h)—NR^(10w)R^(11t)     -   61) —OC(═O)R^(10x)     -   62) —OC(═O)OR^(10y)     -   63) —OC(═O)NR^(10z1)R^(11u)     -   64) —NR^(12i)—NR^(10z2)R^(11v)     -   65) —NR^(10z3)OR^(11w)     -   66) —C(═N—OR^(13a))R^(10a)     -   67) —C(═N—OR^(13b))CHO     -   68) —C(═N—OR^(13c))NR^(10t)R^(11q)     -   69) —C(═N—OR¹³)NR^(12f)—NR^(10u)R^(11r)     -   70) —C(═O)NR^(12j)—S(═O)₂—R^(10a1) and     -   71) —C(═O)NR^(12k)—S(═O)₂—NR^(10a2)R^(11x),         -   substituent group β is a group consisting of     -   1) a halogen atom,     -   2) a hydroxyl group,     -   3) a carboxyl group,     -   4) a cyano group,     -   5) a C₃₋₁₀ alicyclic group,     -   6) a C₁₋₆ alkoxy group,     -   7) a C₃₋₁₀ alicyclic oxy group,     -   8) a C₂₋₆ alkylthio group,     -   9) a 5- or 6-membered heteroarylthio group,     -   10) C₆₋₁₀ aryl,     -   11) 5- or 6-membered heteroaryl,     -   12) a 4- to 10-membered non-aryl heterocycle,     -   13) a C₁₋₆ alkylcarbonyl group,     -   14) a C₃₋₁₀ alicyclic carbonyl group,     -   15) a C₆₋₁₀ arylcarbonyl group,     -   16) a 5- or 6-membered heteroarylcarbonyl group,     -   17) a 4- to 10-membered non-aryl heterocyclyl carbonyl group,     -   18) —NR^(15a)R^(16a),     -   19) —SO₂—NR^(15b)R^(16b),     -   20) —NR^(15c)—C(═O)R^(16e)     -   21) —NR^(17a)—C(═O)NR^(15d)R^(16d),     -   22) —C(═O)NR^(15e)R^(16e),     -   23) —C(═NR^(13g))R^(15f),     -   24) —C(═NR^(13h))NR^(15g)R^(16f)     -   25) —NR^(16g)—C(═NR^(13i))R^(15h)     -   26) —NR^(17b)—C(═NR^(13j))—NR^(15i)R^(16h)     -   27) —(═N—OR^(13g))R^(15f), and     -   28) —C(═N—OR^(13h))NR^(15g)R^(16f)     -   (wherein each substituent from 5) to 17) in substituent group β         is optionally substituted with 1 to 5 substituents selected from         the group consisting of a halogen atom, a hydroxyl group, a         cyano group, a carboxyl group, and —NR^(18a)R^(18b))         -   R^(13s), R^(13b), R^(13c), R^(13d), R^(13e), R^(13f),             R^(13g), R^(13h), R^(13i), R^(13j), and R^(13k) are the same             or different, each independently a hydrogen atom, a hydroxyl             group, a C₁₋₆ alkyl group, or a C₁₋₆ alkoxy group,         -   R^(10a), R^(10b), R^(10c), R^(10d), R^(10e), R^(10f),             R^(10g), R^(10h), R^(10i), R^(10j), R^(10k), R^(10l),             R^(10m), R^(10n), R^(10o), R^(10P), R^(10q), R^(10r),             R^(10s), R^(10t), R^(10u), R^(10v), R^(10w), R^(10x),             R^(10y), R^(10a1), R^(10a2), R^(10z1), R^(10z2), R^(10z3),             R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), R^(11f),             R^(11g), R^(11h), R^(11i), R^(11j), R^(11k), R^(11l),             R^(11m), R^(11n), R^(11o), R^(11p), R^(11q), R^(11r),             R^(11s), R^(11t), R^(11u), R^(11v), R^(11w), R^(11x),             R^(12a), R^(12b), R^(12c), R^(12d), R^(12e), R^(12f),             R^(12g), R^(12h), R^(12i), R^(12j), R^(12k), R¹⁴, R^(15a),             R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g),             R^(15h), R^(15i), R^(16a), R^(16b), R^(16c), R^(16d),             R^(16e), R^(16f), R^(16g), R^(16h), R^(17a), R^(17b),             R^(17c), and R^(17d) are the same or different, each             independently a hydrogen atom, a 5- or 6-membered non-aryl             heterocycle, or a C₁₋₆ alkyl group (wherein the 5- or             6-membered non-aryl heterocycle and the C₁₋₆ alkyl group are             optionally substituted with 1 to 3 of the same or different             substituents, each independently selected from the group             consisting of a hydroxyl group, a cyano group, a C₁₋₆ alkoxy             group, —NR^(18a)R^(18b), a carboxyl group, and             —C(═O)NR^(18c)R^(18d)), and

R^(18a), R^(18b), R^(18c), and R^(18d) are the same or different, each independently a hydrogen atom or a C₁₋₆ alkyl group.

Preferred examples of substituents in “optionally substituted” include the following substituents.

Preferred substituent group α includes

-   -   1) a halogen atom     -   2) a hydroxyl group     -   3) a carboxyl group     -   4) a cyano group     -   5) a C₁₋₆ alkyl group     -   6) a C₁₋₆ alkoxy group     -   7) a C₁₋₆ alkylthio group     -   8) a C₁₋₆ alkylcarbonyl group     -   (wherein each substituent from 5) to 8) is optionally         substituted with 1 to 5 of the same or different substituents         selected from substituent group β)     -   9) a C₃₋₁₀ alicyclic group     -   10) a C₃₋₁₀ alicyclic oxy group     -   11) a C₆₋₁₀ aryloxy group     -   12) a 5- or 6-membered heteroaryloxy group     -   13) a 4- to 10-membered non-aryl heterocyclyl oxy group     -   14) a C₃₋₁₀ alicyclic thio group     -   15) a C₆₋₁₀ arylthio group     -   16) a 5- or 6-membered heteroarylthio group     -   17) a 4- to 10-membered non-aryl heterocyclyl thio group     -   18) C₆₋₁₀ aryl     -   19) 5- or 6-membered heteroaryl     -   20) a 4- to 10-membered non-aryl heterocycle     -   21) a C₃₋₁₀ alicyclic carbonyl group     -   22) a C₆₋₁₀ arylcarbonyl group     -   23) a 5- or 6-membered heteroarylcarbonyl group     -   24) a 4- to 10-membered non-aryl heterocyclyl carbonyl group     -   (wherein each substituent from 9) to 24) is optionally         substituted with 1 to 5 of substituent group f or 1) a C₁₋₆         alkyl group)     -   25) —NR^(10a)R^(11a)     -   26) —SO₂—NR^(10b)R^(11b)     -   27) —NR^(10c)—C(═O)R^(11c)     -   28) —NR^(12a)—C(═O)NR^(10d)R^(11d)     -   29) —NR^(10e)—SO₂—R^(11e)     -   30) —NR^(12b)—SO₂—NR^(10f)R^(11f)     -   31) —C(═O)NR^(10g)R^(11g)     -   32) —C(═NR^(13a))R^(10h)     -   33) —C(═NR^(13b))NR^(10i)R^(11h)     -   34) —NR^(11f)—C(═NR^(13c))R^(10g)     -   35) —NR^(12c)—C(═NR^(13d))—NR^(10j)R^(11i)     -   36) —C(═N—OR^(13a))R^(10h), and     -   37) —C(═N—OR^(13b))NR^(10i)R^(11h),         -   substituent group β is preferably selected from the group             consisting of     -   1) a halogen atom     -   2) a hydroxyl group     -   3) a cyano group     -   4) a C₃₋₁₀ alicyclic group     -   5) a C₁₋₆ alkoxy group     -   6) a C₁₋₆ alkylthio group     -   7) a 5- or 6-membered heteroarylthio group     -   8) 5- or 6-membered heteroaryl     -   9) a 4- to 10-membered non-aryl heterocycle     -   10) a C₁₋₆ alkylcarbonyl group     -   11) a C₃₋₁₀ alicyclic carbonyl group     -   12) a C₆₋₁₀ arylcarbonyl group     -   13) a 5- or 6-membered heteroarylcarbonyl group     -   14) a 4- to 10-membered non-aryl heterocyclyl carbonyl group     -   15) —NR^(15a)R^(16a)     -   16) —NR^(15b)—C(═O)R^(16b)     -   17) —NR^(17a)—C(═O)NR^(15c)R^(16c)     -   18) —C(═O)NR^(15d)R^(16d)     -   19) —C(═NR^(13e))R^(15e)     -   20) —C(═NR^(13f))NR^(15f)R^(16e)     -   21) —NR^(16f)—C(═NR^(13g))R^(15g)     -   22) —NR^(17b)—C(═NR^(13h))—NR^(15h)R^(16g)     -   23) —C(═N—OR^(13e))R^(15e) and     -   24) —C(═N—OR^(13g))NR^(15f)R^(16e)     -   (wherein each substituent from 4) to 14) in substituent group β         is optionally substituted with 1 to S substituents selected from         the group consisting of a halogen atom, a hydroxyl group, a         cyano group, a carboxyl group, and —NR^(18a)R^(18b)),         -   R^(13a), R^(13b), R^(13c), R^(13d), R^(13e), R^(13f),             R^(13g), and R^(13h) are the same or different, each             independently a hydrogen atom, a hydroxyl group, a C₁₋₆             alkyl group, or a C₁₋₆ alkoxy group,         -   R^(10a), R^(10b), R^(10c), R^(10d), R^(10e), R^(10f),             R^(10g), R^(10h), R^(10i), R^(10j), R^(11a), R^(15b),             R^(11c), R^(11d), R^(11e), R^(11e), R^(11f), R^(11g),             R^(11h), R^(11i), R^(12a), R^(12b), R^(12c), R^(15a),             R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g),             R^(15h), R^(16a), R^(16b), R^(16c), R^(16d), R^(16e),             R^(16f), R^(16g), R^(17a), and R^(17b) are the same or             different, each independently a hydrogen atom or a C₁₋₄             alkyl group (wherein the group is optionally substituted             with 1 to 3 of the same or different substituents selected             from a hydroxyl group, a cyano group, C₁₋₆ alkoxy group, and             —NR^(18a)R^(18b)), and         -   R^(18a) and R^(18b) are the same or different, each             independently a hydrogen atom or a C₁₋₆ alkyl group.

More preferred examples of substituents in “optionally substituted” include the following substituents.

More preferred substituent group α includes

-   -   1) a halogen atom     -   2) a hydroxyl group     -   3) a cyano group     -   4) a C₁₋₆ alkyl group     -   5) a C₁₋₆ alkoxy group     -   6) a C₁₋₆ alkylthio group     -   7) a C₁₋₆ alkylcarbonyl group     -   (wherein each substituent from 4) to 7) is optionally         substituted with 1 to 5 of the same or different substituents         selected from substituent group β)     -   8) a 5- or 6-membered heteroaryloxy group     -   9) a 4- to 10-membered non-aryl heterocyclyl oxy group     -   10) a 5- or 6-membered heteroarylthio group     -   11) a 4- to 10-membered non-aryl heterocyclyl thio group     -   12) C₆₋₁₀ aryl     -   13) 5- or 6-membered heteroaryl     -   14) a 4- to 10-membered non-aryl heterocycle     -   (wherein each substituent from 4) to 14) is optionally         substituted with 1 to 5 of substituent group β or 1) a C₁₋₆         alkyl group)     -   15) —NR^(10a)R^(11a)     -   16) —NR^(11b)—C(═O)R^(10b)     -   17) —NR^(12a)—C(═O)NR^(10c)R^(11c)     -   18) —C(═O)NR^(10d)R^(11d)     -   19) —C(═NR^(13a))R^(10e)     -   20) —C(═NR^(13b))NR^(10f)R^(11e)     -   21) —NR^(11f)—C(═NR^(13c))R^(10g)     -   22) —NR^(12b)—C(═NR^(13d))—NR^(10h)R^(11g)     -   23) —C(═N—OR^(13a))R^(10e) and     -   24) —C(═N—OR^(13b))NR^(10f)R^(11e),         -   substituent group β is more preferably     -   1) a halogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) —NR^(15a)R^(16a),     -   5) —NR^(15b)—C(═O) R^(16b),     -   6) —NR^(17a)—C(═O)NR^(15c)R^(16c),     -   7) —C(═O)NR^(15d)R^(16d),     -   8) —C(═NR^(13e))R^(15e),     -   9) —C(═NR^(13f))NR^(15f)R^(16e),     -   10) —NR^(16f)—C(═NR^(13g))R^(15g),     -   11) —NR^(17b)—C(═NR^(13h))—NR^(15h)R^(16g)     -   12) —C(═N—OR^(13e)) R^(15e), or     -   13) —C(═N—OR^(13f))NR^(15f)R^(16e),         -   R^(13a), R^(13b), R^(13c), R^(13d), R^(13e), R^(13f),             R^(13g), and R^(13h) are the same or different, each             independently a hydrogen atom, a hydroxyl group, a C₁₋₆             alkyl group, or a C₁₋₆ alkoxy group,         -   R^(10a), R^(10b), R^(10c), R^(10d), R^(10e), R^(10f),             R^(10g), R^(10h), R^(11a), R^(11b), R^(11c), R^(11d),             R^(11e), R^(11f), R^(11g), R^(12a), R^(12b), R^(15a),             R^(15b), R^(15c), R^(15d), R^(15e), R^(15f), R^(15g),             R^(15h), R^(16a), R^(16b), R^(16c), R^(16d), R^(16e),             R^(16f), R^(16g), R^(17a), and R^(17b) are the same or             different, each independently a hydrogen atom or a C₁₋₆             alkyl group (wherein the group is optionally substituted             with 1 to 3 of the same or different substituents selected             from a hydroxyl group, a cyano group, a C₁₋₆ alkoxy group,             and —NR^(18a)R^(18b)), and         -   R^(18a) and R^(18b) are the same or different, each             independently a hydrogen atom or a C₁₋₆ alkyl group.

“C₁₋₆” means that the number of carbon atoms is 1 to 6. The same applies to other numbers. For example, “C₁₋₄” means that the number of carbon atoms is 1 to 4.

A “heteroatom” refers to an oxygen atom, a nitrogen atom, a sulfur atom, or the like.

A “halogen atom” refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom, preferably a fluorine atom or chlorine atom, and still more preferably a fluorine atom. A “halogen atom” is also referred to as “halogen”.

“C₁₋₆ alkyl group” refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms. “C₁₋₆ alkyl group” is preferably a “C¹⁻⁴ alkyl group”, more preferably a “C₁₋₃ alkyl group”, and still more preferably a “C₁₋₂ alkyl group”. Specific examples of “C₁₋₆ alkyl group” include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, and the like.

“C₂₋₆ alkenyl group” refers to a linear or branched unsaturated hydrocarbon group with 2 to 6 carbon atoms, comprising one or more carbon-carbon double bonds. “C₂₋₉ alkenyl group” is preferably a “C₂₋₄ alkenyl group”. Specific examples of “C₂₋₆ alkenyl group” include, but are not limited to, a vinyl group, 1-propylenyl group, 2-propylenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propylenyl group, 2-methyl-2-propylenyl group, and the like.

“C₂₋₆ alkynyl group” refers to a linear or branched unsaturated aliphatic hydrocarbon group comprising one or more carbon-carbon triple bonds. “C₂₋₆ alkynyl group” is preferably a “C₂₋₄ alkynyl group”. Specific examples thereof include, but are not limited to, an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group, and the like.

“C₃₋₂₀ alicyclic group” refers to a monocyclic or bicyclic non-aromatic hydrocarbon ring with 3 to 20 carbon atoms, including those with a partially unsaturated bond, those with a partially crosslinked structure, those that have a partially spiro form, and those having 1 or 2 carbonyl structures. “Alicyclic group” encompasses cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups. “C₃₋₂₀ alicyclic group” is preferably a “C₃₋₁₀ alicyclic group”, and more preferably a “C₃₋₆ alicyclic group”. Specific examples of “C₃₋₂₀ alicyclic group” include, but are not limited to, a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclohexadinyl group, cycloheptadinyl group, cyclooctadinyl group, adamantyl, norbornyl, and the like.

Specific examples of “C₃₋₂₀ alicyclic group” with a partially crosslinked structure include, but are not limited to, those with a structure shown below and the like.

“C₃₋₂₀ alicyclic group” also encompasses compounds fused to an aromatic ring. Specific examples thereof include the groups represented by the following and the like.

“C₃₋₁₀ alicyclic group” refers to the “C₃₋₂₀ alicyclic group” described above wherein the “C₃₋₁₀ alicyclic group” is a monovalent group.

“C₆₋₁₀ aryl” refers to a monocyclic or bicyclic aromatic hydrocarbon ring with 6 to 10 carbon atoms. Specific examples thereof include a phenyl group, 1-naphthyl group, 2-naphthyl group, and the like. Preferred C₆₋₁₀ aryl includes C₆ aryl and C₁₀ aryl.

“5- or 6-membered heteroaryl” refers to a monocyclic aromatic heterocycle consisting of 5 to 6 atoms, comprising 1 to 4 of the same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom.

“5- to 10-membered heteroaryl” refers to a monocyclic or bicyclic aromatic heterocycle consisting of 5 to 10 atoms, comprising 1 to 4 of the same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom.

“9- or 10-membered heteroaryl” refers to a bicyclic aromatic heterocycle consisting of 9 to 10 atoms, comprising 1 to 4 of the same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom.

“5- or 6-membered nitrogen-containing heteroaryl” refers to a monocyclic aromatic heterocycle consisting of 5 to 6 atoms, comprising 0 to 3 of the same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in addition to 1 nitrogen atom.

Specific examples of “6-membered heteroaryl” include, but are not limited to, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

Specific examples of “5-membered heteroaryl” include, but are not limited to, thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, and the like, 5-membered heteroaryl is preferably triazole, tetrazole, or thiadiazole, and more preferably thiadiazole.

Specific examples of “5- or 6-membered heteroaryl” include the specific examples for “5-membered heteroaryl” and “6-membered heteroaryl” described above.

“4- to 20-membered non-aryl heterocycle” refers to a monocyclic or bicyclic non-aromatic heterocycle comprised of 4 to 20 atoms, comprising 1 to 2 of the same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, including those with a partially unsaturated bond, those with a partially crosslinked structure, and those that have a partially spiro form. A non-aryl heterocycle may form a fused ring with aryl or heteroaryl. When fused to, for example, C₆₋₁₀ aryl or 5- or 6-membered heteroaryl, such a heterocycle is still encompassed by a heterocycle. Such a heterocycle may comprise 1 or 2 carbonyl, thiocarbonyl, sulfinyl, or sulfonyl to make up the non-aryl heterocycle. For example, lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate, cyclic thiocarbamate, and other cyclic groups are also encompassed by said non-aryl heterocycle. In this regard, oxygen atoms of carbonyl, sulfinyl, and sulfonyl and sulfur atoms of thiocarbonyl are not included in the number of 4 to 20 members (size of ring) or the number of heteroatoms constituting the ring. Specific examples of “4- to 20-membered non-aryl heterocycle” include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran, and the like, those with a structure shown below, and the like.

Specific examples of “4- to 20-membered non-aryl heterocycle” with partial crosslinking or spiro structure include, but are not limited to, those with a structure shown below and the like.

“4- to 20-membered nitrogen-containing non-aryl heterocycle” refers to a monocyclic or bicyclic non-aromatic heterocycle comprised of 4 to 20 atoms, comprising 0 or 1 of the same or different heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, in addition to 1 nitrogen atom, including those with a partially unsaturated bond, those with a partially crosslinked structure, and those that have a partially spiro form.

“4- to 10-membered non-aryl heterocycle” refers to the “4- to 20-membered non-aryl heterocycle” described above wherein “4- to 10-membered non-aryl heterocycle” is a monovalent group.

“4- to 10-membered nitrogen-containing non-aryl heterocycle” refers to the “4- to 20-membered nitrogen-containing non-aryl heterocycle” wherein the “4- to 10-membered nitrogen-containing non-aryl heterocycle” is a monovalent group.

“5- to 7-membered non-aryl heterocycle” refers to the “4- to 20-membered non-aryl heterocycle” described above wherein “5- to 7-membered non-aryl heterocycle” is a monovalent group.

“4- to 7-membered non-aryl heterocycle” refers to the “4- to 20-membered non-aryl heterocycle” described above wherein “4- to 7-membered non-aryl heterocycle” is a monovalent group.

Specific examples of “4-membered non-aryl heterocycle” include, but are not limited to, azetidine, oxetane, thietane, and the like.

Specific examples of “4-membered non-aryl heterocycle” with a partially unsaturated bond include, but are not limited to, those with a structure shown below and the like.

Specific examples of “5-membered non-aryl heterocycle” include, but are not limited to, pyrrolidine, pyrrolidone, oxazolidinone, tetrahydrofuran, tetrahydrothiophene, and the like.

Specific examples of “5-membered non-aryl heterocycle” with a partially unsaturated bond include, but are not limited to, those with a structure shown below and the like.

Specific examples of “5-membered non-aryl heterocycle” with a partially crosslinked structure include, but are not limited to, those with a structure shown below and the like.

Specific examples of “5-membered non-aryl heterocycle” comprising carbonyl, thiocarbonyl, or the like include, but are not limited to, those with a structure shown below and the like.

Specific examples of “6-membered non-aryl heterocycle” include, but are not limited to, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrothiopyran, and the like.

Specific examples of “6-membered non-aryl heterocycle” with a partially unsaturated bond include, but are not limited to, those with a structure shown below and the like.

Specific examples of “6-membered non-aryl heterocycle” with a partially crosslinked structure include, but are not limited to, those with a structure shown below and the like.

“C₁₋₆ alkoxy group” refers to a “C₁₋₅ alkyloxy group”, and the C₁₋₆ alkyl moiety is defined the same as the C₁₋₆ alkyl group described above. “C₁₋₆ alkoxy group” is preferably a “C₁₋₄ alkoxy group”, more preferably a “C₁₋₃ alkoxy group”, and still more preferably a “C₁₋₂ alkoxy group”. Specific examples of “C₁₋₆ alkoxy group” include, but are not limited to, a methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1,2-dimethylpropoxy group, and the like.

“C₃₋₁₀ alicyclic oxy group” refers to a (C₃₋₁₀ alicyclic group)-O-group, and the C₃₋₁₀ alicyclic moiety is defined the same as a C₃₋₁₀ alicyclic group. “C₃₋₆ alicyclic oxy group” refers to a (C₃₋₆ alicyclic group)-O-group, and the C₃₋₄ alicyclic moiety is defined the same as a C₃₋₆ alicyclic group. “C₃₋₆ alicyclic oxy group” is preferably a “C₃₋₅ alicyclic oxy group”. Specific examples of “C₃₋₆ alicyclic oxy group” include, but are not limited to, a cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, and the like.

The C₆₋₁₀ aryl moiety of a “C₆₋₁₀ aryloxy group” is defined the same as the C₆₋₁₀ aryl described above. “C₆₋₁₀ aryloxy group” is preferably a “C₆ or C₁₀ aryloxy group”. Specific examples of “C₆₋₁₀ aryloxy group” include, but are not limited to, a phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group, and the like.

The 5- or 6-membered heteroaryl moiety of “5- or 6-membered heteroaryloxy group” is defined the same as the “5-membered heteroaryl” or “6-membered heteroaryl” described above. Specific examples of “5- or 6-membered heteroaryloxy group” include, but are not limited to, a pyrazoyloxy group, triazoyloxy group, thiazoyloxy group, thiadiazoyloxy group, pyridyloxy group, pyridazoyloxy group, and the like.

The 4- to 10-membered non-aryl heterocycle moiety of “4- to 10-membered non-aryl heterocyclyl oxy group” is defined the same as the “4- to 10-membered non-aryl heterocycle” described above. “4- to 10-membered non-aryl heterocyclyl oxy group” is preferably a “4- to 6-membered non-aryl heterocyclyl oxy group”. Specific examples of “4- to 10-membered non-aryl heterocyclyl oxy group” include, but are not limited to, a tetrahydrofuranyloxy group, tetrahydropyranyloxy group, azetidinyloxy group, pyrrolidinyloxy group, piperidinyloxy group, and the like.

The C₁₋₆ alkyl moiety of “C₁₋₆ alkylthio group” is defined the same as the C₁₋₆ alkyl described above. “C₁₋₆ alkylthio group” is preferably a “C₁₋₄ alkylthio group”, and more preferably a “C₁₋₃ alkylthio group”. Specific examples of “C₁₋₆ alkylthio group” include, but are not limited to, a methylthio group, ethylthio group, propylthio group, butylthio group, isopropylthio group, isobutylthio group, tert-butylthio group, sec-butylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1,2-dimethylpropylthio group, and the like.

“C₃₋₁₀ alicyclic thio group” refers to a (C₃₋₁₀ alicyclic group)-S-group, and the C₃₋₁₀ alicyclic moiety is defined the same as the C₃₋₁₀ alicyclic group described above. “C₃₋₁₀ alicyclic thio group” is preferably a “C₃₋₆ alicyclic thio group”. Specific examples of “C₃₋₆ alicyclic thio group” include, but are not limited to, a cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, and the like.

The C₆₋₁₀ aryl moiety of “C₆₋₁₀ arylthio group” is defined the same as the C₆₋₁₀ aryl described above. “C₆₋₁₀ arylthio group” is preferably a “C₆ or C₁₀ arylthio group”. Specific examples of “C₆₋₁₀ aryloxy group” include, but are not limited to, a phenylthio group, 1-naphthylthio group, 2-naphthylthio group, and the like.

The 5- or 6-membered heteroaryl moiety of “5- or 6-membered heteroarylthio group” is defined the same as the “5-membered heteroaryl” or “6-membered heteroaryl” described above. Specific examples of “5- or 6-membered heteroarylthio group” include, but are not limited to, a pyrazoylthio group, triazoylthio group, thiazoylthio group, thiadiazoylthio group, pyridylthio group, pyridazoylthio group, and the like.

The 4- to 10-membered non-aryl heterocycle moiety of “4- to 10-membered non-aryl heterocyclyl thio group” is defined the same as the “4- to 10-membered non-aryl heterocycle” described above. “4- to 10-membered non-aryl heterocyclyl thio group” is preferably a “4- to 6-membered non-aryl heterocyclyl thio group”. Specific examples of “4- to 10-membered non-aryl heterocyclyl thio group” include, but are not limited to, a tetrahydropyranylthio group, piperidinylthio group, and the like.

“C₃₋₁₀ alkylcarbonyl group” refers to a carbonyl group substituted with the “C₁₋₆ alkyl group” described above. “C₁₋₆ alkylcarbonyl group” is preferably a “C₁₋₄ alkylcarbonyl group”. Specific examples of “C₁₋₆ alkylcarbonyl group” include, but are not limited to, an acetyl group, propionyl group, butyryl group, and the like.

“C₃₋₁₀ alicyclic carbonyl group” refers to a carbonyl group substituted with the “C₃₋₁₀ alicyclic group” described above. “C₃₋₁₀ alicyclic carbonyl group” is preferably a “C₃₋₁₀ alicyclic carbonyl group”. Specific examples of “C₃₋₁₀ alicyclic carbonyl group” include, but are not limited to, a cyclopropylcarbonyl group, cyclopentylcarbonyl group, and the like.

“C₆₋₁₀ arylcarbonyl group” refers to a carbonyl group substituted with the “C₆₋₁₀ aryl” described above. “C₆₋₁₀ arylcarbonyl group” is preferably a “C₆ or C₁₀ arylcarbonyl group”. Specific examples of “C₆₋₁₀ arylcarbonyl group” include, but are not limited to, a benzoyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group, and the like.

“5- or 6-membered heteroarylcarbonyl group” refers to a carbonyl group substituted with the “5- or 6-membered heteroaryl” described above. Specific examples of “5- or 6-membered heteroarylcarbonyl group” include, but are not limited to, a pyrazoylcarbonyl group, triazoylcarbonyl group, thiazoylcarbonyl group, thiadiazoylcarbonyl group, pyridylcarbonyl group, pyridazoylcarbonyl group, and the like.

“4- to 10-membered non-aryl heterocyclyl carbonyl group” refers to a carbonyl group substituted with the “4- to 10-membered non-aryl heterocycle” described above. “4- to 10-membered non-aryl heterocyclyl carbonyl group” is preferably a “4- to 6-membered non-aryl heterocyclyl carbonyl group”. Specific examples of “4- to 10-membered non-aryl heterocyclyl carbonyl group” include, but are not limited to, an azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, morpholinylcarbonyl group, and the like.

“C₁₋₆ alkylsulfonyl group” refers to a sulfonyl group substituted with the “C₁₋₆ alkyl group” described above. “C₁₋₆ alkylsulfonyl group” is preferably a “C₁₋₄ alkylsulfonyl group”. Specific examples of “C₁₋₆ alkylsulfonyl group” include, but are not limited to, a methylsulfonyl group, propionylsulfonyl group, butyrylsulfonyl group, and the like.

“C₃₋₁₀ alicyclic sulfonyl group” refers to a sulfonyl group substituted with the “C₃₋₁₀ alicyclic group” described above. “C₃₋₁₀ alicyclic sulfonyl group” is preferably a “C₃₋₆ alicyclic sulfonyl group”. Specific examples of “C₃₋₁₀ alicyclic sulfonyl group” include, but are not limited to, a cyclopropylsulfonyl group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group, and the like.

“C₄₋₁₀ arylsulfonyl group” refers to a sulfonyl group substituted with the “C₆₋₁₀ aryl” described above. “C₆₋₁₀ arylsulfonyl group” is preferably a “C₆ or C₁₀ arylsulfonyl group”. Specific examples of “C₆₋₁₀ arylsulfonyl group” include, but are not limited to, a phenylsulfonyl group, 1-naphthylsulfonyl group, 2-naphthylsulfonyl group, and the like.

“5- or 6-membered heteroarylsulfonyl group” refers to a sulfonyl group substituted with the “5- or 6-membered heteroaryl” described above. Specific examples of “5- or 6-membered heteroarylsulfonyl group” include a pyrazoylsulfonyl group, triazoylsulfonyl group, thiazoylsulfonyl group, thiadiazoylsulfonyl group, pyridylsulfonyl group, pyridazoylsulfonyl group, and the like.

“C₁₋₆ alkylene group” refers to a substituent that is a divalent group due to removing two hydrogen atoms from saturated hydrocarbon with 1 to 6 carbon atoms. “C₁₋₃ alkylene group” and “C₂₋₄ alkylene group” refer to substituents that are divalent groups due to removing two hydrogen atoms from saturated hydrocarbon with 1 to 3 carbon atoms and 2 to 4 carbon atoms, respectively.

“C₃₋₁₀ cycloalkylene group” refers to a substituent that is a divalent group due to removing two hydrogen atoms from saturated cyclic hydrocarbon with 3 to 10 carbon atoms. “C₃₋₆ cycloalkylene group” and “C₄₋₆ cycloalkylene group” refer to substituents that are divalent groups due to removing two hydrogen atoms from saturated cyclic hydrocarbon with 3 to 6 carbon atoms and 4 to 6 carbon atoms, respectively.

“C₆₋₁₀ arylene group” refers to a substituent that is a divalent group due to removing two hydrogen atoms from aromatic hydrocarbon with 6 to 10 carbon atoms. “C₆ arylene group” refers to a substituent that is a divalent group due to removing two hydrogen atoms from aromatic hydrocarbon with 6 carbon atoms.

“5- or 6-membered heteroarylene group” refers to a substituent that is a divalent group due to removing two hydrogen atoms from a 5- or 6-membered heteroaryl ring. “5-membered heteroarylene group” and “6-membered heteroarylene group” refer to substituents that are divalent groups due to removing two hydrogen atoms from 5-membered and 6-membered heteroaryl rings, respectively.

“4- to −10-membered non-aryl heterocyclylene group” refers to a substituent that is a divalent group due to removing two hydrogen atoms from a 4- to 10-membered non-aryl heterocycle. “4- to 5-membered non-aryl heterocyclylene group” and “4- to 6-membered non-aryl heterocyclylene group” refer to substituents that are divalent groups due to removing two hydrogen atoms from 4- to 5-membered and 4- to 6-membered non-aryl heterocycles, respectively.

A bond intersecting a wavy line in the description of a specific structure of R⁵ indicates a bond with L⁴. A bond intersecting a bond between ring atoms means that there are variables (e.g., R^(6a), R^(7a), and the like) at each of the substitutable positions on a monocycle or fused polycycle including the ring atoms. For example, for a monocyclic 5-membered ring (heteroaryl),

(wherein d is 3) is one of

L⁴ attaches to a ring carbon atom of the 5-membered ring. For example, for a monocyclic 6-membered ring (heteroaryl),

(wherein d is 4) is one of

L⁴ attaches to a ring carbon atom of the 6-membered ring. Alternatively, for example, for a monocyclic 5-membered ring (non-aryl heterocycle),

(wherein d is 7) is one of

L⁴ attaches to a ring carbon atom of the 5-membered ring. For example, for a monocyclic 6-membered ring (non-aryl heterocycle),

(wherein d is 10) is one of

L⁴ attaches to a ring carbon atom of the 6-membered ring.

Subscript d is the number of substitutable positions on a ring of R⁵, but is a number of substitutable positions excluding the attachment position to L⁴.

“Bioisostere” refers to another partial structure (functional group) serving the same biological role as a group (e.g., carboxyl group) in a drug molecule (prodrug structures are also encompassed as a concept of a bioisostere in the present invention). “Carboxylic acid isostere” refers to a bioisostere of carboxylic acid. Examples of the carboxylic acid isostere include, but are not limited to, —SO₃H, —SO₂NHR^(19a), —B(OR^(m1))₂, —PO(OR^(m1))(OR^(m2)), —CONHR^(19a), —CONHSO₂R^(19a), —CONR^(19a)CN, —CONHNHSO₂R^(19a), and substituents represented by the formulas (8A), (8B), (8C), (8D), (8E), (8F), (8G), (8H), (8I), (8J), (8K), (8L), (8M), (8N), (8O), (8P), (8Q), (8R), (8S), (8T), (8U), (8V), and (8W) described below (each of the substituents is further optionally substituted with 1 to 3 of the same or different R^(19b) at a chemical substitutable position),

[Chemical Formula 636]

-   -   wherein [in (8V) and (8W),         -   R^(a) is a hydrogen atom, a C₁₋₆ alkyl group, or a C₃₋₁₀             alicyclic group (wherein the C₁₋₆ alkyl group or C₃₋₁₀             alicyclic group is optionally substituted with 1 to 5             halogen atoms),         -   R^(t) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy             group, (wherein the C₁₋₆ alkyl group or C₁₋₆ alkoxy group is             optionally substituted with 1 to 5 halogen atoms), a C₃₋₁₀             alicyclic group, a C₃₋₁₀ alicyclic oxy group, a phenyl             group, a phenoxy group, a pyridyl group, or a pyridyloxy             group, (wherein the C₃₋₁₀ alicyclic group, C₃₋₁₀ alicyclic             oxy group, phenyl group, phenoxy group, pyridyl group, or             pyridyloxy group is optionally substituted with 1 to 5             substituents selected from the group consisting of a halogen             atom, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxy group)],         -   R^(19a) and R^(19b) are the same or different, each             independently representing a hydrogen atom, a hydroxyl             group, a C₁₋₆ alkyl group, C₆₋₁₀ aryl, 5- or 6-membered             heteroaryl, or a 4- to 10-membered non-aryl heterocycle,         -   R^(1m) represents     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl, or     -   6) a 4- to 10-membered non-aryl heterocycle,     -   (wherein each substituent from 2) to 6) is optionally         substituted),         -   wherein if R^(m1) is attached to a boron atom via an oxygen             atom, two R^(m1), as C₂₋₄ alkylene, together with the boron             atom and two oxygen atoms, may form a 5- to 7-membered             non-aryl heterocycle (wherein an alkylene moiety is             optionally substituted in the non-aryl heterocycle), and         -   R^(m2) represents a hydrogen atom, an optionally substituted             C₁₋₆ alkyl group, or an optionally substituted C₃₋₁₀             alicyclic group,     -   wherein, preferably,         -   R^(a) is a hydrogen atom or a C₁₋₆ alkyl group, and     -   R^(t) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy         group, a C₃₋₁₀ alicyclic group, or a C₃₋₁₀ alicyclic oxy group,         or alternatively preferably,     -   R^(19a) and R^(19b) are the same or different, each         independently a hydrogen atom, a hydroxyl group, or a C₁₋₆ alkyl         group, or also preferably     -   R^(m1) and R^(m2) are the same or different, each independently         a hydrogen atom, a C₁₋₆ alkyl group, or a C₃₋₁₀ alicyclic group.

An exemplary embodiment of the compounds of the invention is a compound represented by formula (1a) or (1b):

-   -   or a pharmaceutically acceptable salt thereof,     -   wherein         -   G is an oxygen atom, a sulfur atom, or —NR^(a1)—,         -   X is a hydroxyl group, an optionally substituted C₁₋₆ alkoxy             group, or —NR^(a2)R^(b1),         -   R^(a1), R^(a2), and R^(b1) are the same or different, each             independently     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl     -   5) 5- or 6-membered heteroaryl,     -   6) a 4- to 10-membered non-aryl heterocycle,     -   7) a C₁₋₆ alkylcarbonyl group,     -   8) a C₃₋₁₀ alicyclic carbonyl group,     -   9) a C₆₋₁₀ arylcarbonyl group,     -   10) a 5- or 6-membered heteroarylcarbonyl group,     -   11) a C₁₋₆ alkylsulfonyl group,     -   12) a C₃₋₁₀ alicyclic sulfonyl group,     -   13) a C₆₋₁₀ arylsulfonyl group,     -   14) a 5- or 6-membered heteroarylsulfonyl group, or     -   15) —OR^(c1),     -   (wherein each substituent from 2) to 14) is optionally         substituted),         -   wherein R^(a2) and R^(b1) together may form an optionally             substituted 4- to 10-membered nitrogen-containing non-aryl             heterocycle,         -   R^(c1) is     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl, or     -   6) a 4- to 10-membered non-aryl heterocycle,     -   (wherein each substituent from 2) to 6) is optionally         substituted),         -   L¹ is a single bond, an oxygen atom, a sulfur atom, —SO—,             —SO₂—, —NR^(d)—, —NR^(d)C(═O)—, or —NR^(d)SO₂—,         -   L² is a single bond or an optionally substituted C₁₋₆             alkylene group,         -   Z is     -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) a carboxyl group,     -   5) a C₃₋₁₀ alicyclic group,     -   6) C₆₋₁₀ aryl,     -   7) 5- or 6-membered heteroaryl,     -   8) a 4- to 10-membered non-aryl heterocycle,     -   9) a C₁₋₆ alkoxy group,     -   10) a C₃₋₁₀ alicyclic oxy group,     -   11) a C₆₋₁₀ aryloxy group,     -   12) a 5- or 6-membered heteroaryloxy group,     -   13) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   14) a C₁₋₆ alkylthio group,     -   15) a C₃₋₁₀ alicyclic thio group,     -   16) a C₆₋₁₀ arylthio group,     -   17) a 5- or 6-membered heteroarylthio group,     -   18) a 4- to 10-membered non-aryl heterocyclyl thio group,     -   (wherein each substituent from 5) to 18) is optionally         substituted),     -   19) —SO₂—NR^(e1)R^(f1),     -   20) —NR^(e1)—C(═O)OR^(f1),     -   21) —NR^(g1)—C(═O)NR^(e1)R^(f1),     -   22) —NR_(e1)—C(═S)R^(f1),     -   23) —NR^(e1)—C(═S)OR^(f1),     -   24) —NR^(g1)—C(═S)NR^(e1)R^(f1),     -   25) —NR^(g1)—CR^(e1) (═NR^(f1)),     -   26) —NR^(g1)—CR^(e1)(═N—OR^(f1)),     -   27) —NR^(h1)—C(═NR^(g1))NR^(e1)R^(f1),     -   28) —NR^(h1)—C(═N—OR^(g1))NR^(e1)R^(f1),     -   29) —NR^(1i)—C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   30) —NR^(1i)—C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   31) —NR^(e1)—SO₂—R^(f1),     -   32) —NR^(g1)—SO₂—NR^(e1)R^(f1),     -   33) —C(═O)OR^(e1),     -   34) —C(═S)OR^(e1),     -   35) —C(═S)NRO^(e1)R^(f1),     -   36) —C(═S)NR^(e1)OR^(f1),     -   37) —C(═S)NR^(g1)—NR^(e1)R^(f1),     -   38) —C(═NR^(e1))R^(f1),     -   39) —C(═N—OR^(e1))R^(f1),     -   40) —C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   41) —C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   42) —NR^(e1)R^(f1),     -   43) —NR^(g1)—NR^(e1)R^(f1),     -   44) —NR^(e1)OR^(f1),     -   45) —NR^(e1)—C(═O)R^(f1),     -   46) —C(═O)NR^(e1)R^(f1),     -   47) —C(═O)NR^(e1)OR^(f1),     -   48) —C(═O)NR^(g1)—NR^(e1)R^(f1),     -   49) —C(═O)R^(e1),     -   50) —C(═NR^(g1))NR^(e1)R^(f1), or     -   51) —C(═N—OR^(h1))NR^(e1)R^(f1),         -   one of R¹, R², and R³ is formula (2):

-   -   wherein,         -   Y is an oxygen atom, a sulfur atom, or —NR^(j)—,         -   ring A is an optionally substituted 4- to 20-membered             non-aryl heterocycle,         -   L³ is —C(═O)—, —S(═O)—, or —S(═O)₂—,         -   L⁴ is     -   1) a single bond,     -   2) a C₁₋₄ alkylene group,     -   3) a C₃₋₁₀ cycloalkylene group,     -   4) a C₆₋₁₀ arylene group,     -   5) a 5- or 6-membered heteroarylene group,     -   6) a 4- to 10-membered non-aryl heterocyclylene group, or     -   7) —C(═N—OR^(h1))—,     -   (wherein each substituent from 2) to 6) is optionally         substituted), and         -   R⁵ is     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) a 4- to 10-membered non-aryl heterocycle,     -   5) C₆₋₁₀ aryl,     -   6) 5- or 6-membered heteroaryl,     -   7) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 2) to 7) is optionally         substituted), or     -   8) —NR^(e1)OH,         -   the remaining two (without the structure of formula (2)             among R¹, R², and R³) are the same or different, each             independently a hydrogen atom, a halogen atom, an optionally             substituted C₃₋₆ alkyl group, an optionally substituted C₁₋₆             alkoxy group, an optionally substituted C₁₋₆ alkylthio             group, an optionally substituted 5- or 6-membered             heteroaryl, or —NR^(a3)R^(b2),         -   R^(d), R^(e1), R^(e2), R^(f1), R^(f2), R^(g1), R^(g2),             R^(h1), R^(h2), R^(i1), R^(i2), and R^(j) are the same or             different, each independently a hydrogen atom, an optionally             substituted C₁₋₆ alkyl group, an optionally substituted             C₃₋₁₀ alicyclic group, optionally substituted C₆₋₁₀ aryl,             optionally substituted 5- or 6-membered heteroaryl, or an             optionally substituted 4- to 10-membered non-aryl             heterocycle,         -   a combination of R^(e1) and R^(f1) or R^(e2) and R^(f2),             when attached to the same nitrogen atom, together may form             an optionally substituted 4- to 10-membered             nitrogen-containing non-aryl heterocycle,         -   R⁴ is     -   1) —C(═O)R⁸,     -   2) —SO₂-L⁶-R⁸,     -   (wherein R⁸ in 1) and 2) is —NR^(a5)R^(b4),         —NR^(a5)-L⁷-B(OR^(a1))₂, —OR^(m1), or an optionally substituted         C₁₋₆ alkyl group, and L⁶ is a single bond or —NR^(a6)—),     -   3) —NR^(a4)R^(b3),     -   4) —B(OR^(a1))₂,     -   5) —PO(OR^(m1))(OR^(m2)),     -   6) optionally substituted 5-membered heteroaryl,     -   7) an optionally substituted 5-membered non-aryl heterocycle, or     -   8) a bioisostere of one of 1) to 7),     -   (wherein the formulas of 2), 4), 5), and 6) include a carboxylic         acid isostere, and 8) may include them in duplicates),         -   R^(a3), R^(a4), R^(a5), R^(a6), R^(b2), R^(b3), and R^(b4)             are the same or different, each independently having the             same definition as R^(a1), R^(a2), and R^(b1), wherein a             combination of R^(a3) and R^(b2), R^(M) and R^(b3), or             R^(a5) and R^(b4), when attached to the same nitrogen atom,             together may form an optionally substituted 4- to             10-membered nitrogen-containing non-aryl heterocycle,         -   R^(m1) is     -   1) a hydrogen atom,     -   2) a C₂₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) C₆₋₁₀ aryl,     -   5) 5- or 6-membered heteroaryl, or     -   6) a 4- to 10-membered non-aryl heterocycle,     -   (wherein each substituent from 2) to 6) is optionally         substituted),         -   wherein if R^(a1) is attached to a boron atom via an oxygen             atom, two R^(m1), as C₂₋₄ alkylene, together with the boron             atom and two oxygen atoms, may form a 5- to 7-membered             non-aryl heterocycle (wherein an alkylene moiety is             optionally substituted in the non-aryl heterocycle),         -   R^(m2) is a hydrogen atom, an optionally substituted C₁₋₆             alkyl group, or an optionally substituted C₃₋₁₀ alicyclic             group, and         -   L⁷ is an optionally substituted C₁₋₃ alkylene group.

In some embodiments, Z-L²-L¹ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted C₁₋₆ alkylthio group. In one embodiment, L¹ is a single bond.

In some embodiments, L² is a single bond or an optionally substituted C₁₋₆ alkylene group. In one embodiment, L² is a single bond.

In some embodiments, Z is

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) a carboxyl group,     -   5) a C₃₋₁₀ alicyclic group,     -   6) C₆₋₁₀ aryl,     -   7) 5- or 6-membered heteroaryl,     -   8) a 4- to 10-membered non-aryl heterocycle,     -   9) a C₁₋₆ alkoxy group,     -   10) a C₃₋₁₀ alicyclic oxy group,     -   11) a C₆₋₁₀ aryloxy group,     -   12) a 5- or 6-membered heteroaryloxy group,     -   13) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   14) a C₁₋₆ alkylthio group,     -   15) a C₃₋₁₀ alicyclic thio group,     -   16) a C₆₋₁₀ arylthio group,     -   17) a 5- or 6-membered heteroarylthio group,     -   18) a 4- to 10-membered non-aryl heterocyclyl thio group,     -   (wherein each substituent from 5) to 18) is optionally         substituted),     -   19) —SO₂—NR^(e1)R^(f1),     -   20) —NR^(e1)—C(═O)OR^(f1),     -   21) —NR^(g1)—C(═O)NR^(e1)R^(f1),     -   22) —NR^(e1)—C(═S)R^(f1),     -   23) —NR^(e1)—C(═S)OR^(f1),     -   24) —NR^(g1)—C(═S)NR^(e1)R^(f1),     -   25) —NR^(g1)—CR^(e1)(═NR^(f1)),     -   26) —NR^(g1)—CR^(e1)(═N—OR^(f1)),     -   27) —NR^(h1)—C(═NR^(g1))NR^(e1)R^(f1),     -   28) —NR^(h1)—C(═N—OR^(g1))NR^(e1)R^(f1),     -   29) —NR^(i1)—C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   30) —NR^(i1)—C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   31) —NR^(e1)—SO₂—R^(f1),     -   32) —NR^(g1)—SO₂—NR^(e1)R^(f1),     -   33) —C(═O)OR^(e1),     -   34) —C(═S)OR^(e1),     -   35) —C(═S)NR^(e1)R^(f1),     -   36) —C(═S)NR^(e1)OR^(f1),     -   37) —C(═S)NR^(g1)—NR^(e1)R^(f1),     -   38) —C(═NR^(e1))R^(f1),     -   39) —C(═N—OR^(e1))R^(f1),     -   40) —C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   41) —C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1),     -   42) —NR^(e1)R^(f1),     -   43) —NR^(g2)—NR^(e1)R^(f1),     -   44) —NR^(e1)OR^(f1),     -   45) —NR^(e1)—C(═O)R^(f1),     -   46) —C(═O)NR^(e1)R^(d1),     -   47) —C(═O)NR^(e1)OR^(f1),     -   48) —C(═O)NR^(g2)—NR^(e1)R^(f1),     -   49) —C(═O)R^(e1),     -   50) —C(═NR^(g1))NR^(e1)R^(f1), or     -   51) —C(═N—OR^(h1))NR^(e1)R^(f1).     -   The R^(e1), R^(f1), R^(g1), and R^(h1) are the same as the         definitions herein. In a preferred embodiment, Z is one of 1),         2), 5) to 8), 39), and 42). In one embodiment, Z is a hydrogen         atom. Alternatively, in another embodiment, Z is an optionally         substituted C₁₋₆ alkylthio group. In still another embodiment, Z         is an optionally substituted C₁₋₆ alkyl group.

In a preferred embodiment, Z-L²-L¹ is a hydrogen atom. Alternatively, in another embodiment, Z-L²-L¹ is an optionally substituted C₁₋₆ alkylthio group. In still another embodiment, Z-L²-L¹ is an optionally substituted C₂₋₆ alkyl group.

In some embodiments, G is an oxygen atom, a sulfur atom, or —NR^(a1)—. In one embodiment, G is an oxygen atom or a sulfur atom. In a preferred embodiment, G is an oxygen atom. The R^(a1) is the same as the definition herein.

In some embodiments, X is a hydroxyl group, an optionally substituted C₁₋₆ alkoxy group, or —NR²R^(b1). In one embodiment, X is a hydroxyl group or an optionally substituted C₁₋₆ alkoxy group. In a preferred embodiment, X is a hydroxyl group. The R^(a2) and R^(b1) are the same as the definitions herein.

In some embodiments, one of R¹, R², and R³ is a group represented by formula (2):

-   -   wherein         -   Y is an oxygen atom, a sulfur atom, or —NR^(j)—,         -   ring A is an optionally substituted 4- to 20-membered             non-aryl heterocycle,         -   L³ is —C(═O)—, —S(═O)—, or —S(═O)₂—,         -   L⁴ is     -   1) a single bond,     -   2) a C₁₋₄ alkylene group,     -   3) a C₃₋₁₀ cycloalkylene group,     -   4) a C₆₋₁₀ arylene group     -   5) a 5- or 6-membered heteroarylene group,     -   6) a 4- to 10-membered non-aryl heterocyclylene group, or     -   7) —C(═N—OR^(h1))—,     -   (wherein each substituent from 2) to 6) is optionally         substituted), and         -   R⁵ is     -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) a 4- to 10-membered non-aryl heterocycle,     -   5) C₆₋₁₀ aryl,     -   6) 5- or 6-membered heteroaryl,     -   7) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 2) to 7) is optionally         substituted), or     -   8) —NR^(e1)OH], and         -   the remaining two (without the structure of formula (2)             among R¹, R², and R³) are the same or different, each             independently a hydrogen atom, a halogen atom, an optionally             substituted C₃₋₆ alkyl group, an optionally substituted C₁₋₆             alkoxy group, an optionally substituted C₁₋₆ alkylthio             group, optionally substituted 5- or 6-membered heteroaryl,             or —NR^(a3)R^(b2), wherein R^(a3) and R^(b2) are the same as             the definitions herein. In a preferred embodiment, R³ has             the structure of formula (2).

In one embodiment, if R⁵ in formula (2) is 2) a C₁₋₆ alkyl group, 3) a C₃₋₁₀ alicyclic group, 4) a 4- to 10-membered non-aryl heterocycle, 5) C₃₋₁₀ aryl, 6) 5- or 6-membered heteroaryl, or 7) a C₁₋₆ alkylthio group, 2), 3), 4), 5), 6), and 7) are optionally substituted with a carboxyl group or a C₁₋₆ alkyl group substituted with a carboxyl group. In one embodiment, said 2), 3), 4), 5), 6), and 7) are optionally substituted with a carboxyl group. In one embodiment, said 2), 3), 4), 5), 6), and 7) are optionally substituted with a C₁₋₆ alkyl group substituted with a carboxyl group.

In one embodiment, if one of R¹, R², and R³ is represented by formula (2), the remaining two without the structure of formula (2) among R¹, R², and R³ are each independently selected from the group consisting of a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy. In a preferred embodiment, R³ is represented by formula (2), and R¹ and R^(Z) are each independently selected from the group consisting of a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

In some embodiments, Y is an oxygen atom, a sulfur atom, or —NR^(j)—. In one embodiment, Y is an oxygen atom or a sulfur atom. In a preferred embodiment, Y is an oxygen atom. The R^(j) is the same as the definition herein.

In some embodiments, ring A is an optionally substituted 4- to 20-membered non-aryl heterocycle. In one embodiment, ring A is an optionally substituted 4- to 10-membered non-aryl heterocycle. In one embodiment, ring A is an optionally substituted 4- to 7-membered non-aryl heterocycle. In one embodiment, ring A is an optionally substituted 4- to 7-membered nitrogen-containing non-aryl heterocycle. In one embodiment, ring A is an optionally substituted 4- to 6-membered non-aryl heterocycle. In one embodiment, ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle. In one embodiment, ring A is an optionally substituted azetidine ring. In a specific embodiment of said embodiment, ring A is

-   -   wherein R⁶ represents a substituent on an azetidine ring and is         defined the same as R^(6a), a bond that is orthogonal to a wavy         line indicates a bond with Y, and a bond with * indicates a bond         with L³. In a preferred embodiment, R⁶ are the same or         different, each independently selected from the group consisting         of     -   1) a hydrogen atom,     -   2) a halogen atom,     -   3) a C₁₋₆ alkyl group, and     -   4) a C₁₋₆ alkoxy group     -   (wherein each of substituents 3) and 4) is optionally         substituted with a halogen atom), and in a preferred embodiment,         are selected from the group consisting of     -   1) a hydrogen atom,     -   2) a halogen atom, and     -   3) a C₁₋₆ alkyl group optionally substituted with a halogen         atom, and     -   most preferably are hydrogen atoms.

In a specific embodiment, ring A is

wherein m is 1, 2, or 3, n is 1, 2, or 3, m+n is 2, 3, 4, or 5, a bond that is orthogonal to a wavy line indicates a bond with Y, and a bond with * indicates a bond with L³. In one embodiment, m+n is 2, 3, or 4. In one embodiment, m+n is 2 or 3. In a preferred embodiment, m+n is 2. In a more preferred embodiment, m=1 and n=1.

In some embodiments, L³ is —C(═O)—, —S(═O)—, or —S(═O)₂—. In one embodiment, L³ is —C(═O) — or —S(═O)₂—. In a preferred embodiment, L³ is —C(═O)—.

In some embodiments, L⁴ is

-   -   1) a single bond,     -   2) a C₁₋₆ alkylene group,     -   3) a C₃₋₁₀ cycloalkylene group,     -   4) a C₆₋₁₀ arylene group     -   5) a 5- or 6-membered heteroarylene group,     -   6) a 4- to 10-membered non-aryl heterocyclylene group, or     -   7) —C(═N—OR^(h1))—,     -   (wherein each substituent from 2) to 6) is optionally         substituted).     -   In one embodiment, L⁴ is a single bond, —C(═N—OR^(h1))— or an         optionally substituted C₁₋₆ alkylene group, wherein R^(h1) is an         optionally substituted C₁₋₆ alkyl group. In one embodiment, L⁴         is a single bond or a C₁₋₆ alkylene group optionally substituted         with —NR²¹R²² or ═NOR²³, wherein R²¹, R²², and R²³ are each         independently a hydrogen atom, an optionally substituted C₁₋₆         alkyl group, or an optionally substituted 4- to 10-membered         non-aryl heterocyclyl carbonyl group. In a preferred embodiment,         L⁴ is a bond, —CH₂—, —CH(NH₂)—, or —CH(NH₂)—CH₂—, wherein if an         amino group is present in L⁴, carbon that attaches to the amino         group attaches to L³.

In one embodiment, L⁴ is a single bond, —CH₂—, —CMe (NH₂)—, —CH(NHMe)—, —CD(NH₂)— (wherein D represents a heavy hydrogen atom), —CH(NH₂)—, or —CH₂CH₂—. In one embodiment, L⁴ is a single bond, —CH₂—, or —CH(NH₂)—.

In one embodiment, L⁴ is

-   -   1) —(CH₂)_(p)—CR¹⁰(NHR¹¹)—,     -   2) —(CH₂)_(q)—CR¹²R¹³—, or     -   3) —(CH₂)_(p)—CR¹⁰(NHR¹¹) —(CH₂)_(q)—CR¹²R¹³—, wherein p and q         are independently 0 or 1, R¹⁰ is     -   1) a hydrogen atom,     -   2) a carboxyl group, or     -   3) —C(═O)NR^(10a)R^(10b),     -   R¹¹ is     -   1) a hydrogen atom,     -   2) —C(═O)R^(11a), or     -   3) an optionally substituted 5- or 6-membered non-aryl         heterocyclyl carbonyl group,     -   wherein if R¹⁰ is —C(═O)NR^(10a)R^(10b), R^(10b) and R¹¹         together may form —CH₂CH₂—,     -   R¹² is     -   1) a hydrogen atom, or     -   2) an optionally substituted C₁₋₄ alkyl group,     -   R¹³ is     -   1) a hydrogen atom,     -   2) a hydroxyl group     -   3) an optionally substituted C₁₋₄ alkyl group     -   4) a sulfanyl group,     -   5) a carboxyl group,     -   6) an optionally substituted C₁₋₄ alkylthio group,     -   7) —NR^(13a)R^(13b),     -   8) —NR^(13a)—C(═O)R^(13b),     -   9) an optionally substituted 5- or 6-membered non-aryl         heterocyclyl carbonylamino group,     -   10) —NR^(13a)—C(═O)NR^(13b)R^(13c),     -   11) —C(═O)NR^(13a)R^(13b),     -   12) —C(═O)NR^(13a)OR^(13b),     -   13) —S(═O)₂—R^(13a),     -   14) —S(═O)₂—NR^(13a)R^(13b),     -   15) —C(═O)NR¹—S(═O)₂—R^(13b), or     -   16) —C(═O)NR¹³—S(═O)₂—NR^(13b)R^(13c), and     -   R^(10a), R^(10b), R^(11a), R^(13a), R^(13b), and R^(13c) are         each independently a hydrogen atom or an optionally substituted         C₁₋₄ alkyl group.

In one embodiment, L⁴ is —CH(NH₂)—CHR¹³—, wherein carbon that attaches to the NH₂ attaches to L³,

-   -   R⁵ is a hydrogen atom, and     -   R²³ is     -   1) —NH—C(═O)CH₃,     -   2) —NH—C(═O)NH₂,     -   3) —NH—C(═O)CH(NH₂)—CH₂C(═O)NH₂,     -   4) —NH—C(═O)CH₂—NH₂,     -   5) —NH—C(═O)CH(NH₂)—CH₂OH, or     -   6) a pyrrolidin-2-ylcarbonylamino group.

In one embodiment, L⁴ is —CH(NH₂)—CR¹²R¹³—, wherein carbon that attaches to the NH₂ attaches to L³,

-   -   R⁵ is a hydrogen atom or methyl,     -   R¹² is a hydrogen atom or methyl, and     -   R¹³ is a benzylthio group or a sulfanyl group.

In one embodiment, L⁴ is —CH(NH₂) —(CH₂)—CR¹²R¹³—, wherein q is 0 or 1, and carbon that attaches to the NH₂ attaches to L³,

-   -   R⁵ is a hydrogen atom, and     -   R¹³ is     -   1) a carboxyl group,     -   2) —C(═O)NH₂,     -   3) —C(═O)NH(CH₃),     -   4) —C(═O)N(CHO)₂,     -   5) —C(═O)NH—(CH₂)₂—OH,     -   6) —C(═O)NH—(CH₂)₂—NH₂,     -   7) —C(═O)NH—S(═O)₂—CH₃,     -   8) —C(═O)NHOH,     -   9) —S(═O)₂—NH₂,     -   10) —S(═O)₂—CH₃, or     -   11) a hydroxyl group.

In one embodiment, L⁴ is —CH(NHR¹¹)—CH₂—, wherein carbon that attaches to the NHR¹¹ attaches to L³,

-   -   R⁵ is hydrogen, and     -   R¹¹ is     -   1) —C(═O)CH(NH₂)—CH₂C(═O)NH₂,     -   2) —C(═O)CH₂—NH₂,     -   3) —C(═O)CH(CH₃) —NH₂,     -   4) —C(═O)CH(NH₂)—CH₂OH, or     -   5) pyrrolidin-2-ylcarbonyl.

In one embodiment, L⁴ is —CH(NHR¹¹)—CH(COOH)—, wherein carbon that attaches to the NHR¹¹ attaches to L³,

-   -   R⁵ is hydrogen, and     -   R¹¹ is     -   1) —C(═O)CH(NH₂)—CH₂C(═O)NH₂,     -   2) —C(═O)CH₂—NH₂,     -   3) —C(═O)CH(CH₃) —NH₂,     -   4) —C(═O)CH(NH₂)—CH₂OH, or     -   5) pyrrolidin-2-ylcarbonyl.

In one embodiment, L⁴ is —CHR¹³— or —CH₂—CHR¹³—,

-   -   R⁵ is hydrogen, and     -   R¹³ is —C(═O)NH₂ or —C(═O)NHOH.

In one embodiment, L⁴ is —CH₂—CR¹⁰ (NH₂)—, and the CH₂ group attaches to L³,

-   -   R⁵ is hydrogen, and     -   R¹⁰ is a carboxy group or —C(═O)NH₂.

In one embodiment, L⁴ is —(CH₂)_(p)—CR¹⁰ (NHR¹¹)—(CH₂)_(q)—CHR¹³— or —CHR¹³—(CH₂)_(q)—CR¹⁰(NHR¹¹)—(CH₂)_(p)—, wherein q is 0 or 1, R⁵ is hydrogen,

-   -   (1) if L⁴ is —CHR¹³—(CH₂)_(q)—CR¹⁰(NHR¹¹)—(CH₂)_(p)—, carbon of         the —CHR¹³— group attaches to L³,     -   p is 0,     -   R¹⁰ is a hydrogen atom, a carboxyl group, or —C(═O)NHR^(10b),     -   R¹¹ is a hydrogen atom,     -   R^(10b) is a hydrogen atom,     -   wherein if R¹⁰ is —C(═O)NHR^(10b), R^(10b) and R¹¹ together may         form —CH₂CH₂—, and     -   R¹³ is a hydrogen atom, and     -   (2) if L⁴ is —(CH₂)_(p)—CR¹⁰ (NHR^(f1)) —(CH₂)_(q)—CHR¹³—,         carbon of the —(CH₂)_(p)— group attaches to L³,     -   p is 1,     -   R¹⁰ and R¹¹ are both hydrogen atoms,     -   R¹³ is a carboxyl group or —C(═O)NR^(13a)R^(13b), and     -   R^(13a) and R^(13b) are each independently a hydrogen atom or an         optionally substituted C₁₋₄ alkyl group.

In one embodiment, L⁴ is —CR¹²(NH₂)—,

-   -   R¹² is a hydrogen atom or a methyl group, and     -   R⁵ is a C₁₋₄ alkyl group optionally substituted with a hydroxyl         group.

In some embodiments, R⁵ is

-   -   1) a hydrogen atom,     -   2) a C₁₋₆ alkyl group,     -   3) a C₃₋₁₀ alicyclic group,     -   4) a 4- to 10-membered non-aryl heterocycle,     -   5) C₆₋₁₀ aryl,     -   6) 5- or 6-membered heteroaryl,     -   7) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 2) to 7) is optionally         substituted), or     -   8) —NR^(e1)OH.         In one embodiment, R⁵ is a hydrogen atom, an optionally         substituted C₁₋₆ alkyl group, an optionally substituted 4- to         10-membered non-aryl heterocycle, optionally substituted C₆₋₁₀         aryl, optionally substituted 5- or 6-membered heteroaryl, an         optionally substituted C₁₋₆ alkylthio group, or —NR^(e1)OH,         wherein R^(e1) is a hydrogen atom or an optionally substituted         C₁₋₆ alkyl group. In one embodiment, R⁵ is an optionally         substituted 5- or 6-membered heteroaryl or optionally         substituted C₆₋₁₀ aryl.

In one embodiment, R⁵ is optionally substituted 5- or 6-membered heteroaryl. In one embodiment, R⁵ is an optionally substituted 4- to 10-membered non-aryl heterocycle. In one embodiment, R⁵ is a hydrogen atom or an optionally substituted C₆₋₁₀ alkyl group.

In one embodiment, R⁵ is selected from the group consisting of

-   -   subscript d is the number of substitutable positions on a ring         of R⁵,     -   each R^(6a) is independently selected from the group consisting         of     -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) a nitro group,     -   5) halogen,     -   6) a C₁₋₄ alkyl group,     -   7) a C₃₋₁₀ alicyclic group,     -   8) a C₁₋₄ alkoxy group,     -   9) a C₃₋₁₀ alicyclic oxy group,     -   10) a C₆₋₁₀ aryloxy group,     -   11) a 5- or 6-membered heteroaryloxy group,     -   12) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   (wherein each substituent from 6) to 12) is optionally         substituted),     -   13) —SO₂—NR^(e2)R^(f2),     -   14) —NR^(g2)—CR^(e2)(═NR^(f2)),     -   15) —NR^(g2)—CR^(e2) (═N—OR^(f2)),     -   16) —NR^(h2)—C(═NR^(g2))NR^(e2)R^(f2),     -   17) —NR^(h2)—C(═N—OR^(g2))NR^(e2)R^(f2),     -   18) —NR^(i2)—C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   19) —NR^(i2)—C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   20) —C(═NR^(e2))R^(f2),     -   21) —C(═N—OR^(e2))R^(f2),     -   22) —C(═NR^(h2)) —NR^(e2)R^(f2),     -   23) —C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   24) —C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   25) —NR^(e2)R^(f2),     -   26) —NR^(g2)—NR^(e2)R^(f2),     -   27) —NR^(e2)OR^(f2),     -   28) —NR^(e2)—C(═O)R^(f2),     -   29) —C(═O)NR^(e2)R^(f2),     -   30) —C(═O)NR^(e2)OR^(f2),     -   31) —C(═O)NR^(g2)—NR^(e2)R^(f2),     -   32) —C(═O)R^(e2),     -   33) —C(═O)OR^(e2), and     -   34) —C(═N—OR^(h2))NR^(e2)R^(f2), and         -   each R^(6b) is independently selected from the group             consisting of     -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted),     -   4) a C₃₋₁₀ alicyclic group     -   (wherein the alicyclic group is optionally substituted),     -   5) —C(═NR^(e2))R^(f2),     -   6) —C(═N—OR^(e2))R^(f2),     -   7) —SO₂—NR^(e2)R^(f2),     -   8) —C(═NR^(h2))—NR^(e2)R^(f2),     -   9) —C(═NR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   10) —C(═N—OR^(h2))NR^(g2)—NR^(e2)R^(f2),     -   11) —C(═O)NR^(e2)R^(f2),     -   12) —C(═O)NR^(e2)OR^(f2),     -   13) —C(═O)NR^(g2)—NR^(e2)R^(f2),     -   14) —C(═O)R^(e2), and     -   15) —C(═N—OR^(h2))NR^(e2)R^(f2).

In one embodiment, R⁵ is 5- or 6-membered aryl or heteroaryl selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each —R^(6a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) halogen,     -   4) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e2)R^(f2), a 5- or 6-membered non-aryl heterocycle, —C(═O)         OR^(f2), or a hydroxyl group),     -   5) a C₁₋₄ alkoxy group     -   6) —NR^(e2)R^(f2), and     -   7) —C(═O)OR^(e2), and     -   each R^(6b) is independently selected from the group consisting         of     -   1) a hydrogen atom,     -   2) a hydroxyl group, and     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e2)R^(f2), —C(═O)NR^(e2)R^(f2), —C(═O) OR^(f2), or a         hydroxyl group).

In one embodiment, R^(e2) and R^(f2) are the same or different, each independently a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted C₃₋₁₀ alicyclic group. In one embodiment, R^(e2) and R^(f2) are the same or different, each independently a hydrogen atom or an optionally substituted C₁₋₆ alkyl group. In one embodiment, R^(e2) and R^(f2) are hydrogen atoms. In one embodiment, R^(6a) is —NR^(e2)R^(f2), and one of R^(e2) and R^(f2) is a hydrogen atom and the other is a C₁₋₄ alkyl group (wherein the alkyl group is optionally substituted with an amino group or a hydroxyl group).

In one embodiment, each R^(6a) may be independently halogen.

In one embodiment, each R^(6a) may be independently an alkylamino group substituted with an amino group. In one embodiment, each R^(6a) may be independently NR^(e2)R^(f2), wherein R^(e2) is a C₁₋₆ alkyl group, the C₁₋₆ alkyl group is substituted with —NR^(10a)R^(11a), and R^(10a) and R^(11a) are each independently defined the same as the description herein.

In one embodiment, each R^(6a) may be independently —C(═O)OH.

In one embodiment, each R^(6a) and/or each R^(6b) may be independently an alkyl group substituted with a carboxyl group. In one embodiment, each R^(6a) and/or each R^(6b) may be independently a C₁₋₄ alkyl group substituted with a —C(═O)OH group.

In one embodiment, R⁵ is a 4- to 6-membered non-aryl heterocycle selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(7a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a cyano group,     -   4) halogen,     -   5) a C₁₋₄ alkyl group,     -   6) a C₃₋₁₀ alicyclic group,     -   7) a C₁₋₄ alkoxy group,     -   8) a C₃₋₁₀ alicyclic oxy group,     -   9) a C₆₋₁₀ aryloxy group,     -   10) a 5- or 6-membered heteroaryloxy group,     -   11) a 4- to 10-membered non-aryl heterocyclyl oxy group,     -   (wherein each substituent from 5) to 11) is optionally         substituted),     -   12) —SO₂—NR^(e3)R^(f3),     -   13) —NR^(g2)—CR^(e3)(═NR^(f3)),     -   14) —NR^(g2)—CR^(e3)(N—OR^(f3)),     -   15) —NR^(h2)—C(═NR^(g2))NR^(e3)R^(f3),     -   16) —NR^(h2)—C(═N—OR^(g2))NR^(e3)R^(f3),     -   17) —NR^(i2)—C(═NR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   18) —NR^(i2)—C(═N—OR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   19) —C(═NR^(e3)) R^(f3),     -   20) —C(═N—OR^(e3))R^(f3),     -   21) —C(═NR^(h2))—NR^(e3)R^(f3),     -   22) —C(═NR^(h2))NR^(g3)—NR^(e3)R^(f3),     -   23) —C(═N—OR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   24) —NR^(e3)R^(f3),     -   25) —NR^(f2)—NR^(e3)R^(f3),     -   26) —NR^(e3)OR^(f3),     -   27) —NR^(e3)—C(═O)R^(f3),     -   28) —C(═O)NR^(e3)R^(f3),     -   29) —C(═O)NR^(e3)OR^(f3),     -   30) —C(═O)NR^(g2)—NR^(e3)R^(f3),     -   31) —C(═O)R^(e3),     -   32) —C(═O)OR^(e3), and     -   33) —C(═N—OR^(h2))NR^(e3)R^(f3),     -   each R^(7b) is independently selected from the group consisting         of     -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted),     -   4) a C₃₋₁₀ alicyclic group     -   (wherein the alicyclic group is optionally substituted),     -   5) —C(═NR^(e3))R^(f3),     -   6) —C(═N—OR^(e3))R^(f3),     -   7) —SO₂—NR^(e3)R^(f3),     -   8) —C(═NR^(h2)) —NR^(e3)R^(f3),     -   9) —C(═NR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   10) —C(═N—OR^(h2))NR^(g2)—NR^(e3)R^(f3),     -   11) —C(═O)NR^(e3)R^(f3),     -   12) —C(═O)NR^(e3)OR^(f3),     -   13) —C(═O)NR^(g2)—NR^(e3)R^(f3),     -   14) —C(═O) R^(e3), and     -   15) —C(═N—OR^(h2))NR^(e3)R^(f3), and         -   R^(e3) and R^(f3) are defined the same as R^(e2) and R^(f2)             according to item B1.

In one embodiment, R⁵ is a 4- to 6-membered non-aryl heterocycle selected from the group consisting of

subscript d is the number of substitutable positions on a ring of R⁵,

each R^(7a) is independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a hydroxyl group,     -   3) halogen,     -   4) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with     -   NR^(e3)R^(f3), a 5- or 6-membered non-aryl heterocycle,         —C(═O)OR^(f3), or a hydroxyl group),     -   5) a C₁₋₄ alkoxy group     -   6) —NR^(e3)R^(f3),     -   7) —C(═O)OR^(e3),     -   8) C₆₋₁₀ aryl, and     -   9) —C(═O)NR^(e3)R^(f3),         -   each R^(7b) is independently selected from the group             consisting of     -   1) a hydrogen atom,     -   2) a hydroxyl group, and     -   3) a C₁₋₄ alkyl group     -   (wherein the alkyl group is optionally substituted with         NR^(e3)R^(f3), —C(═O) OR^(f3), or a hydroxyl group), and         -   R^(e3) and R^(f3) are defined the same as R^(e2) and R^(f2)             according to any one of items B38 to B40.

In some embodiments, if one of R¹, R², and R³ is represented by formula (2), the remaining two are the same or different, each independently a hydrogen atom, a halogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkoxy group, an optionally substituted C₁₋₆ alkylthio group, optionally substituted 5- or 6-membered heteroaryl, or —NR^(a3)R^(b2), wherein R^(a3) and R^(b2) are the same as the descriptions herein. In a preferred embodiment, R³ is represented by formula (2).

In one embodiment where R³ is represented by formula (2), R¹ and R² are the same or different, each independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a halogen atom,     -   3) a C₁₋₆ alkyl group,     -   4) a C₁₋₆ alkoxy group, and     -   5) a C₁₋₆ alkylthio group,     -   (wherein each substituent from 3) to 5) is optionally         substituted).

In said embodiment, R¹ and R² are the same or different, each independently selected from the group consisting of

-   -   1) a hydrogen atom,     -   2) a halogen atom, and     -   3) an optionally substituted C₁₋₆ alkyl group.     -   In a preferred embodiment, R¹ and R² are both hydrogen atoms.

In some embodiments, R⁴ in formulas (1a) and (1b) is

-   -   1) —C(═O)R⁸,     -   2) —SO₂-L⁶-R⁸,     -   (wherein R⁸ in 1) and 2) is —NR^(a5)R^(b4),         —NR^(a5)-L⁷-B(OR^(m1))₂, —OR^(m1), or an optionally substituted         C₁₋₆ alkyl group, and L⁶ is a single bond or —NR^(a6)—),     -   3) —NR^(a4)R^(b3),     -   4) —B(OR^(m1))₂,     -   5) —PO(OR^(m1))(OR^(m2)),     -   6) optionally substituted 5-membered heteroaryl,     -   7) an optionally substituted 5-membered non-aryl heterocycle, or     -   8) a bioisostere of one of 1) to 7),     -   (wherein the formulas of 2), 4), 5), and 6) include a carboxylic         acid isostere, and 8) may include them in duplicates).         In one embodiment, R⁴ is —C(═O)—OR^(m1) or a carboxylic acid         isostere thereof. In a preferred embodiment, R⁴ is 1) —COOH         (i.e., a carboxyl group), or 2) a carboxylic acid isostere. The         R^(a4), R^(a5), R^(a6), R^(b3), R^(b4), L⁷, R^(m1), and R^(m2)         are the same as the definitions herein.

A specific example of a specific embodiment of the compound of the invention includes a compound represented by formula (3a) or (3b):

or a pharmaceutically acceptable salt thereof. X, R¹, R², and R³ in formula (3a) or (3b) are defined the same as the definitions herein, and R⁴ is selected from the group consisting of

-   -   1) —COOR^(m1) (wherein R^(m1) is a hydrogen atom, a C₁₋₆ alkyl         group, a C₃₋₁₀ alicyclic group, C₆₋₁₀ aryl, 5- or 6-membered         heteroaryl, or a 4- to 10-membered non-aryl heterocycle, wherein         the C₁₋₆ alkyl group, the C₃₋₁₀ alicyclic group, the C₆₋₁₀ aryl,         the 5- or 6-membered heteroaryl, and the 4- to 10-membered         non-aryl heterocycle are each optionally substituted), and     -   2) a bioisostere of 1).     -   In a preferred embodiment, R⁴ is 1) —COOH (i.e., a carboxyl         group) or 2) a carboxylic acid isostere.

A specific example of a preferred embodiment of the compound of the invention includes compounds represented by formulas (4a) and (4b):

or a pharmaceutically acceptable salt thereof. X, R⁴, Y, ring A, L³, L⁴, and R⁵ in formulas (4a) and (4b) are defined the same as the definitions herein, and R¹ and R² are the same or different, each independently a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, or a C₁₋₆ alkoxy group (wherein the C₁₋₄ alkyl group and C₁₋₆ alkoxy group are optionally substituted with 1 to 5 halogens).

A specific example of a still more preferred embodiment of the compound of the invention includes compounds represented by formulas (5a) and (5b):

or a pharmaceutically acceptable salt thereof. R¹, R², Y, L³, L⁴, R⁵, and ring A in formulas (5a) and (5b) are defined the same as the definitions herein, and ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.

A specific example of a yet still more preferred embodiment of the compound of the invention includes compounds represented by formulas (6a) and (6b):

or a pharmaceutically acceptable salt thereof. L³, L⁴, and R⁵ in formulas (6a) and (6b) are defined the same as the definitions herein, m is an integer 1, 2, or 3, n is an integer 1, 2, or 3, and m+n is 2, 3, or 4. In one embodiment, m is 1 or 2, n is 1 or 2, and m+n is 2 or 3. In a preferred embodiment, m is 1, and n is 1.

A specific example of a preferred embodiment of the compound of the invention includes the following compound: a compound represented by

or a pharmaceutically acceptable salt thereof, wherein R^(ZL) is a substituent selected from the group consisting of the Z1 to Z4 described below,

-   -   one of R¹, R², and R³ is

and the remaining two are hydrogen atoms, linking group L^(a) is a substituent selected from the group consisting of L1 to L36 described below, and substituent Q^(a) is a substituent selected from the group consisting of Q1 to Q103 described below;

R^(2L):

linking group L^(a):

substituent Q^(a):

A specific example of a more preferred embodiment of the compound of the invention includes a compound of the following formula:

-   -   a compound represented by

or a pharmaceutically acceptable salt thereof, wherein R^(ZL) is a substituent selected from the group consisting of

-   -   Z1 to Z4 described above,     -   R¹ and R² are hydrogen atoms, and     -   R³ is

wherein linking group L^(a) is a substituent selected from the group consisting of L1 to L36 described above, and substituent Q^(a) is a substituent selected from the group consisting of Q1 to Q103 described above.

Examples of a more preferred embodiment of the compound of the invention include the compounds of the following Table (1) or a pharmaceutically acceptable salt thereof.

TABLE 1 Example R^(ZL) L* Q* 1 Z1 L1 Q1 2 Z1 L1 Q2 3 Z1 L1 Q3 4 Z1 L1 Q4 5 Z1 L1 Q5 6 Z1 L1 Q6 7 Z1 L1 Q7 8 Z1 L1 Q8 9 Z1 L1 Q9 10 Z1 L1 Q10 11 Z1 L1 Q11 12 Z1 L1 Q12 13 Z1 L1 Q13 14 Z1 L1 Q14 15 Z1 L1 Q15 16 Z1 L1 Q16 17 Z1 L1 Q17 18 Z1 L1 Q18 19 Z1 L1 Q19 20 Z1 L1 Q20 21 Z1 L1 Q21 22 Z1 L1 Q22 23 Z1 L1 Q23 24 Z1 L1 Q24 25 Z1 L1 Q25 26 Z1 L1 Q26 27 Z1 L1 Q27 28 Z1 L1 Q28 29 Z1 L1 Q29 30 Z1 L1 Q30 31 Z1 L1 Q31 32 Z1 L1 Q32 33 Z1 L1 Q33 34 Z1 L1 Q34 35 Z1 L1 Q35 36 Z1 L1 Q36 37 Z1 L1 Q37 38 Z1 L1 Q38 39 Z1 L1 Q39 40 Z1 L2 Q1 41 Z1 L2 Q2 42 Z1 L2 Q3 43 Z1 L2 Q4 44 Z1 L2 Q5 45 Z1 L2 Q6 46 Z1 L2 Q7 47 Z1 L2 Q8 48 Z1 L2 Q9 49 Z1 L2 Q10 50 Z1 L2 Q11 51 Z1 L2 Q12 52 Z1 L2 Q13 53 Z1 L2 Q14 54 Z1 L2 Q15 55 Z1 L2 Q16 56 Z1 L2 Q17 57 Z1 L2 Q18 58 Z1 L2 Q19 59 Z1 L2 Q20 60 Z1 L2 Q21 61 Z1 L2 Q22 62 Z1 L2 Q23 63 Z1 L2 Q24 64 Z1 L2 Q25 65 Z1 L2 Q26 66 Z1 L2 Q27 67 Z1 L2 Q28 68 Z1 L2 Q29 69 Z1 L2 Q30 70 Z1 L2 Q31 71 Z1 L2 Q32 72 Z1 L2 Q33 73 Z1 L2 Q34 74 Z1 L2 Q35 75 Z1 L2 Q36 76 Z1 L2 Q37 77 Z1 L2 Q38 78 Z1 L2 Q39 79 Z1 L3 Q1 80 Z1 L3 Q2 81 Z1 L3 Q3 82 Z1 L3 Q4 83 Z1 L3 Q5 84 Z1 L3 Q6 85 Z1 L3 Q7 86 Z1 L3 Q8 87 Z1 L3 Q9 88 Z1 L3 Q10 89 Z1 L3 Q11 90 Z1 L3 Q12 91 Z1 L3 Q13 92 Z1 L3 Q14 93 Z1 L3 Q15 94 Z1 L3 Q16 95 Z1 L3 Q17 96 Z1 L3 Q18 97 Z1 L3 Q19 98 Z1 L3 Q20 99 Z1 L3 Q21 100 Z1 L3 Q22 101 Z1 L3 Q23 102 Z1 L3 Q24 103 Zł L3 Q25 104 Z1 L3 Q26 105 Z1 L3 Q27 106 Z1 L3 Q28 107 Z1 L3 Q29 108 Z1 L3 Q30 109 Z1 L3 Q31 110 Z1 L3 Q32 111 Z1 L3 Q33 112 Z1 L3 Q34 113 Z1 L3 Q35 114 Z1 L3 036 115 Z1 L3 Q37 116 Z1 L3 Q38 117 Z1 L3 Q39 118 Z1 L4 Q1 119 Z1 L4 Q2 120 Z1 L4 Q3 121 Z1 L4 Q4 122 Z1 L4 Q5 123 Z1 L4 Q6 124 Z1 L4 Q7 125 Z1 L4 Q8 126 Z1 L4 Q9 127 Z1 L4 Q10 128 Z1 L4 Q11 129 Z1 L4 Q12 130 Z1 L4 Q13 131 Z1 L4 Q14 132 Z1 L4 Q15 133 Z1 L4 Q16 134 Z1 L4 Q17 135 Z1 L4 Q18 136 Z1 L4 Q19 137 Z1 L4 Q20 138 Z1 L4 Q21 139 Z1 L4 Q22 140 Z1 L4 Q23 141 Z1 L4 Q24 142 Z1 L4 Q25 143 Z1 L4 Q26 144 Z1 L4 Q27 145 Z1 L4 Q28 146 Z1 L4 Q29 147 Z1 L4 Q30 148 Z1 L4 Q31 149 Z1 L4 Q32 150 Z1 L4 Q33 151 Zł L4 Q34 152 Z1 L4 Q35 153 Z1 L4 Q36 154 Z1 L4 Q37 155 Z1 L4 Q38 156 Z1 L4 Q39 157 Z1 L5 Q1 158 Z1 L5 Q2 159 Z1 L5 Q3 160 Z1 L5 Q4 161 Z1 L5 Q5 162 Z1 L5 Q6 163 Z1 L5 Q7 164 Z1 L5 Q8 165 Z1 L5 Q9 166 Z1 L5 Q10 167 Z1 L5 Q11 168 Z1 L5 Q12 169 Z1 L5 Q13 170 Z1 L5 Q14 171 Z1 L5 Q15 172 Z1 L5 Q16 173 Z1 L5 Q17 174 Z1 L5 Q18 175 Z1 L5 Q19 176 Z1 L5 Q20 177 Z1 L5 Q21 178 Z1 L5 Q22 179 Z1 L5 Q23 180 Z1 L5 Q24 181 Z1 L5 Q25 182 Z1 L5 Q26 183 Z1 L5 Q27 184 Z1 L5 Q28 185 Z1 L5 Q29 186 Z1 L5 Q30 187 Z1 L5 Q31 188 Z1 L5 Q32 189 Z1 L5 Q33 190 Z1 L5 Q34 191 Z1 L5 Q35 192 Z1 L5 Q36 193 Z1 L5 Q37 194 Z1 L5 Q38 195 Z1 L5 Q39 196 Z1 L6 Q1 197 Zł L6 Q2 198 Z1 L6 Q3 199 Z1 L6 Q4 200 Z1 L6 Q5 201 Z1 L6 Q6 202 Z1 L6 Q7 203 Z1 L6 Q8 204 Z1 L6 Q9 205 Z1 L6 Q10 206 Z1 L6 Q11 207 Z1 L6 Q12 208 Z1 L6 Q13 209 Z1 L6 Q14 210 Z1 L6 Q15 211 Z1 L6 Q16 212 Z1 L6 Q17 213 Z1 L6 Q18 214 Z1 L6 Q19 215 Z1 L6 Q20 218 Z1 L6 Q21 217 Z1 L6 Q22 218 Z1 L6 Q23 219 Z1 L6 Q24 220 Z1 L6 Q25 221 Z1 L6 Q26 222 Z1 L6 Q27 223 Z1 L6 Q28 224 Z1 L6 Q29 225 Z1 L6 Q30 226 Z1 L6 Q31 227 Z1 L6 Q32 228 Z1 L6 Q33 229 Z1 L6 Q34 230 Z1 L6 Q35 231 Z1 L6 Q36 232 Z1 L6 Q37 233 Z1 L6 Q38 234 Z1 L6 Q39 235 Z1 L7 Q1 236 Z1 L7 Q2 237 Z1 L7 Q3 238 Z1 L7 Q4 239 Z1 L7 Q5 240 Z1 L7 Q6 241 Z1 L7 Q7 242 Z1 L7 Q8 243 Z1 L7 Q9 244 Z1 L7 Q10 245 Z1 L7 Q11 246 Z1 L7 Q12 247 Z1 L7 Q13 248 Z1 L7 Q14 249 Z1 L7 Q15 250 Z1 L7 Q16 251 Z1 L7 Q17 252 Z1 L7 Q18 253 Z1 L7 Q19 254 Z1 L7 Q20 255 Z1 L7 Q21 256 Z1 L7 Q22 257 Z1 L7 Q23 258 Z1 L7 Q24 259 Z1 L7 Q25 260 Z1 L7 Q26 261 Z1 L7 Q27 262 Z1 L7 Q28 263 Z1 L7 Q29 264 Z1 L7 Q30 265 Z1 L7 Q31 266 Z1 L7 Q32 267 Z1 L7 Q33 268 Z1 L7 Q34 269 Z1 L7 Q35 270 Z1 L7 Q36 271 Z1 L7 Q37 272 Z1 L7 Q38 273 Z1 L7 Q39 274 Z1 L8 Q1 275 Z1 L8 Q2 276 Z1 L8 Q3 277 Z1 L8 Q4 278 Z1 L8 Q5 279 Z1 L8 Q6 280 Z1 L8 Q7 281 Z1 L8 Q8 282 Z1 L8 Q9 283 Z1 L8 Q10 284 Z1 L8 Q11 285 Z1 L8 Q12 286 Z1 L8 Q13 287 Z1 L8 Q14 288 Z1 L8 Q15 289 Z1 L8 Q16 290 Z1 L8 Q17 291 Z1 L8 Q18 292 Z1 L8 Q19 293 Z1 L8 Q20 294 Z1 L8 Q21 295 Z1 L8 Q22 296 Z1 L8 Q23 297 Z1 L8 Q24 298 Z1 L8 Q25 299 Z1 L8 Q26 300 Z1 L8 Q27 301 Z1 L8 Q28 302 Z1 L8 Q29 303 Z1 L8 Q30 304 Z1 L8 Q31 305 Z1 L8 Q32 306 Z1 L8 Q33 307 Z1 L8 Q34 308 Z1 L8 Q35 309 Z1 L8 Q36 310 Z1 L8 Q37 311 Z1 L8 Q38 312 Z1 L8 Q39 313 Z1 L9 Q1 314 Z1 L9 Q2 315 Z1 L9 Q3 316 Z1 L9 Q4 317 Z1 L9 Q5 318 Z1 L9 Q6 319 Z1 L9 Q7 320 Z1 L9 Q8 321 Z1 L9 Q9 322 Z1 L9 Q10 323 Z1 L9 Q11 324 Z1 L9 Q12 325 Z1 L9 Q13 326 Z1 L9 Q14 327 Z1 L9 Q15 328 Z1 L9 Q16 329 Z1 L9 Q17 330 Z1 L9 Q18 331 Z1 L9 Q19 332 Z1 L9 Q20 333 Z1 L9 Q21 334 Z1 L9 Q22 335 Z1 L9 Q23 336 Z1 L9 Q24 337 Z1 L9 Q25 338 Z1 L9 Q26 339 Z1 L9 Q27 340 Z1 L9 Q28 341 Z1 L9 Q29 342 Z1 L9 Q30 343 Z1 L9 Q31 344 Z1 L9 Q32 345 Z1 L9 Q33 346 Z1 L9 Q34 347 Z1 L9 Q35 348 Z1 L9 Q36 349 Z1 L9 Q37 350 Z1 L9 Q38 351 Z1 L9 Q39 352 Z1 L10 Q1 353 Z1 L10 Q2 354 Z1 L10 Q3 355 Z1 L10 Q4 356 Z1 L10 Q5 357 Z1 L10 Q6 358 Z1 L10 Q7 359 Z1 L10 Q8 360 Z1 L10 Q9 361 Z1 L10 Q10 362 Z1 L10 Q11 363 Z1 L10 Q12 364 Z1 L10 Q13 365 Z1 L10 Q14 366 Z1 L10 Q15 367 Z1 L10 Q16 368 Z1 L10 Q17 369 Z1 L10 Q18 370 Z1 L10 Q19 371 Z1 L10 Q20 372 Z1 L10 Q21 373 Z1 L10 Q22 374 Z1 L10 Q23 375 Z1 L10 Q24 376 Z1 L10 Q25 377 Z1 L10 Q26 378 Z1 L10 Q27 379 Z1 L10 Q28 380 Z1 L10 Q29 381 Z1 L10 Q30 382 Z1 L10 Q31 383 Z1 L10 Q32 384 Z1 L10 Q33 385 Z1 L10 Q34 386 Z1 L10 Q35 387 Z1 L10 Q36 388 Z1 L10 Q37 389 Z1 L10 Q38 390 Z1 L10 Q39 391 Z1 L11 Q1 392 Z1 L11 Q2 393 Z1 L11 Q3 394 Z1 L11 Q4 395 Z1 L11 Q5 396 Z1 L11 Q6 397 Z1 L11 Q7 398 Z1 L11 Q8 399 Z1 L11 Q9 400 Z1 L11 Q10 401 Z1 L11 Q11 402 Z1 L11 Q12 403 Z1 L11 Q13 404 Z1 L11 Q14 405 Z1 L11 Q15 406 Z1 L11 Q16 407 Z1 L11 Q17 408 Z1 L11 Q18 409 Z1 L11 Q19 410 Z1 L11 Q20 411 Z1 L11 Q21 412 Z1 L11 Q22 413 Z1 L11 Q23 414 Z1 L11 Q24 415 Z1 L11 Q25 416 Z1 L11 Q26 417 Z1 L11 Q27 418 Z1 L11 Q28 419 Z1 L11 Q29 420 Z1 L11 Q30 421 Z1 L11 Q31 422 Z1 L11 Q32 423 Z1 L11 Q33 424 Z1 L11 Q34 425 Z1 L11 Q35 426 Z1 L11 Q36 427 Z1 L11 Q37 428 Z1 L11 Q38 429 Z1 L11 Q39 430 Z1 L12 Q1 431 Z1 L12 Q2 432 Z1 L12 Q3 433 Z1 L12 Q4 434 Z1 L12 Q5 435 Z1 L12 Q6 436 Z1 L12 Q7 437 Z1 L12 Q8 438 Z1 L12 Q9 439 Z1 L12 Q10 440 Z1 L12 Q11 441 Z1 L12 Q12 442 Z1 L12 Q13 443 Z1 L12 Q14 444 Z1 L12 Q15 445 Z1 L12 Q16 446 Z1 L12 Q17 447 Z1 L12 Q18 448 Z1 L12 Q19 449 Z1 L12 Q20 450 Z1 L12 Q21 451 Z1 L12 Q22 452 Z1 L12 Q23 453 Z1 L12 Q24 454 Z1 L12 Q25 455 Z1 L12 Q26 456 Z1 L12 Q27 457 Z1 L12 Q28 458 Z1 L12 Q29 459 Z1 L12 Q30 460 Z1 L12 Q31 461 Z1 L12 Q32 462 Z1 L12 Q33 463 Z1 L12 Q34 464 Z1 L12 Q35 465 Z1 L12 Q36 466 Z1 L12 Q37 467 Z1 L12 Q38 468 Z1 L12 Q39 469 Z1 L13 Q1 470 Z1 L13 Q2 471 Z1 L13 Q3 472 Z1 L13 Q4 473 Z1 L13 Q5 474 Z1 L13 Q6 475 Z1 L13 Q7 476 Z1 L13 Q8 477 Z1 L13 Q9 478 Z1 L13 Q10 479 Z1 L13 Q11 480 Z1 L13 Q12 481 Z1 L13 Q13 482 Z1 L13 Q14 483 Z1 L13 Q15 484 Z1 L13 Q16 485 Z1 L13 Q17 486 Z1 L13 Q18 487 Z1 L13 Q19 488 Z1 L13 Q20 489 Z1 L13 Q21 490 Z1 L13 Q22 491 Z1 L13 Q23 492 Z1 L13 Q24 493 Z1 L13 Q25 494 Z1 L13 Q26 495 Z1 L13 Q27 498 Z1 L13 Q28 497 Z1 L13 Q29 498 Z1 L13 Q30 499 Z1 L13 Q31 500 Z1 L13 Q32 501 Z1 L13 Q33 502 Z1 L13 Q34 503 Z1 L13 Q35 504 Z1 L13 Q36 505 Z1 L13 Q37 506 Z1 L13 Q38 507 Z1 L13 Q39 508 Z1 L14 Q1 509 Z1 L14 Q2 510 Z1 L14 Q3 511 Z1 L14 Q4 512 Z1 L14 Q5 513 Z1 L14 Q6 514 Z1 L14 Q7 515 Z1 L14 Q8 516 Z1 L14 Q9 517 Z1 L14 Q10 518 Z1 L14 Q11 519 Z1 L14 Q12 520 Z1 L14 Q13 521 Z1 L14 Q14 522 Z1 L14 Q15 523 Z1 L14 Q16 524 Z1 L14 Q17 525 Z1 L14 Q18 526 Z1 L14 Q19 527 Z1 L14 Q20 528 Z1 L14 Q21 529 Z1 L14 Q22 530 Z1 L14 Q23 531 Z1 L14 Q24 532 Z1 L14 Q25 533 Z1 L14 Q26 534 Z1 L14 Q27 535 Z1 L14 Q28 536 Z1 L14 Q29 537 Z1 L14 Q30 538 Z1 L14 Q31 539 Z1 L14 Q32 540 Z1 L14 Q33 541 Z1 L14 Q34 542 Z1 L14 Q35 543 Z1 L14 Q36 544 Z1 L14 Q37 545 Z1 L14 Q38 546 Z1 L14 Q39 547 Z1 L1 Q1 548 Z1 L1 Q2 549 Z2 L1 Q3 550 Z2 L1 Q4 551 Z2 L1 Q5 552 Z2 L1 Q6 553 Z2 L1 Q7 554 Z2 L1 Q8 555 Z2 L1 Q9 556 Z2 L1 Q10 557 Z2 L1 Q11 558 Z2 L1 Q12 559 Z2 L1 Q13 560 Z2 L1 Q14 561 Z2 L1 Q15 562 Z2 L1 Q16 563 Z2 L1 Q17 564 Z2 L1 Q18 565 Z2 L1 Q19 566 Z2 L1 Q20 567 Z2 L1 Q21 568 Z2 L1 Q22 569 Z2 L1 Q23 570 Z2 L1 Q24 571 Z2 L1 Q25 572 Z2 L1 Q26 573 Z2 L1 Q27 574 Z2 L1 Q28 575 Z2 L1 Q29 576 Z2 L1 Q30 577 Z2 L1 Q31 578 Z2 L1 Q32 579 Z2 L1 Q33 580 Z2 L1 Q34 581 Z2 L1 Q35 582 Z2 L1 Q36 583 Z2 L1 Q37 584 Z2 L1 Q38 585 Z2 L1 Q39 586 Z2 L2 Q1 587 Z2 L2 Q2 588 Z2 L2 Q3 589 Z2 L2 Q4 590 Z2 L2 Q5 591 Z2 L2 Q6 592 Z2 L2 Q7 593 Z2 L2 Q8 594 Z2 L2 Q9 595 Z2 L2 Q10 596 Z2 L2 Q11 597 Z2 L2 Q12 598 Z2 L2 Q13 599 Z2 L2 Q14 600 Z2 L2 Q15 601 Z2 L2 Q16 602 Z2 L2 Q17 603 Z2 L2 Q18 604 Z2 L2 Q19 605 Z2 L2 Q20 606 Z2 L2 Q21 607 Z2 L2 Q22 608 Z2 L2 Q23 609 Z2 L2 Q24 610 Z2 L2 Q25 611 Z2 L2 Q26 612 Z2 L2 Q27 613 Z2 L2 Q28 614 Z2 L2 Q29 615 Z2 L2 Q30 616 Z2 L2 Q31 617 Z2 L2 Q32 618 Z2 L2 Q33 619 Z2 L2 Q34 620 Z2 L2 Q35 621 Z2 L2 Q36 622 Z2 L2 Q37 623 Z2 L2 Q38 624 Z2 L2 Q39 625 Z2 L3 Q1 626 Z2 L3 Q2 627 Z2 L3 Q3 628 Z2 L3 Q4 629 Z2 L3 Q5 630 Z2 L3 Q6 631 Z2 L3 Q7 632 Z2 L3 Q8 633 Z2 L3 Q9 634 Z2 L3 Q10 635 Z2 L3 Q11 636 Z2 L3 Q12 637 Z2 L3 Q13 638 Z2 L3 Q14 639 Z2 L3 Q15 640 Z2 L3 Q16 641 Z2 L3 Q17 642 Z2 L3 Q18 643 Z2 L3 Q19 644 Z2 L3 Q20 645 Z2 L3 Q21 646 Z2 L3 Q22 647 Z2 L3 Q23 648 Z2 L3 Q24 649 Z2 L3 Q25 650 Z2 L3 Q26 651 Z2 L3 Q27 652 Z2 L3 Q28 653 Z2 L3 Q29 654 Z2 L3 Q30 655 Z2 L3 Q31 656 Z2 L3 Q32 657 Z2 L3 Q33 658 Z2 L3 Q34 659 Z2 L3 Q35 660 Z2 L3 Q36 661 Z2 L3 Q37 662 Z2 L3 Q38 663 Z2 L3 Q39 664 Z2 L4 Q1 665 Z2 L4 Q2 666 Z2 L4 Q3 667 Z2 L4 Q4 668 Z2 L4 Q5 689 Z2 L4 Q6 670 Z2 L4 Q7 671 Z2 L4 Q8 672 Z2 L4 Q9 673 Z2 L4 Q10 674 Z2 L4 Q11 675 Z2 L4 Q12 676 Z2 L4 Q13 677 Z2 L4 Q14 678 Z2 L4 Q15 679 Z2 L4 Q16 680 Z2 L4 Q17 681 Z2 L4 Q18 682 Z2 L4 Q19 683 Z2 L4 Q20 684 Z2 L4 Q21 685 Z2 L4 Q22 686 Z2 L4 Q23 687 Z2 L4 Q24 688 Z2 L4 Q25 689 Z2 L4 Q26 690 Z2 L4 Q27 691 Z2 L4 Q28 692 Z2 L4 Q29 693 Z2 L4 Q30 694 Z2 L4 Q31 695 Z2 L4 Q32 696 Z2 L4 Q33 697 Z2 L4 Q34 698 Z2 L4 Q35 699 Z2 L4 Q36 700 Z2 L4 Q37 701 Z2 L4 Q38 702 Z2 L4 Q39 703 Z2 L5 Q1 704 Z2 L5 Q2 705 Z2 L5 Q3 706 Z2 L5 Q4 707 Z2 L5 Q5 708 Z2 L5 Q6 709 Z2 L5 Q7 710 Z2 L5 Q8 711 Z2 L5 Q9 712 Z2 L5 Q10 713 Z2 L5 Q11 714 Z2 L5 Q12 715 Z2 L5 Q13 716 Z2 L5 Q14 717 Z2 L5 Q15 718 Z2 L5 Q16 719 Z2 L5 Q17 720 Z2 L5 Q18 721 Z2 L5 Q19 722 Z2 L5 Q20 723 Z2 L5 Q21 724 Z2 L5 Q22 725 Z2 L5 Q23 726 Z2 L5 Q24 727 Z2 L5 Q25 728 Z2 L5 Q26 729 Z2 L5 Q27 730 Z2 L5 Q28 731 Z2 L5 Q29 732 Z2 L5 Q30 733 Z2 L5 Q31 734 Z2 L5 Q32 735 Z2 L5 Q33 736 Z2 L5 Q34 737 Z2 L5 Q35 738 Z2 L5 Q36 739 Z2 L5 Q37 740 Z2 L5 Q38 741 Z2 L5 Q39 742 Z2 L6 Q1 743 Z2 L6 Q2 744 Z2 L6 Q3 745 Z2 L6 Q4 746 Z2 L6 Q5 747 Z2 L6 Q6 748 Z2 L6 Q7 749 Z2 L6 Q8 750 Z2 L6 Q9 751 Z2 L6 Q10 752 Z2 L6 Q11 753 Z2 L6 Q12 754 Z2 L6 Q13 755 Z2 L6 Q14 756 Z2 L6 Q15 757 Z2 L6 Q16 758 Z2 L6 Q17 759 Z2 L6 Q18 760 Z2 L6 Q19 761 Z2 L6 Q20 762 Z2 L6 Q21 763 Z2 L6 Q22 764 Z2 L6 Q23 765 Z2 L6 Q24 766 Z2 L6 Q25 767 Z2 L6 Q26 768 Z2 L6 Q27 769 Z2 L6 Q28 770 Z2 L6 Q29 771 Z2 L6 Q30 772 Z2 L6 Q31 773 Z2 L6 Q32 774 Z2 L6 Q33 775 Z2 L6 Q34 776 Z2 L6 Q35 777 Z2 L6 Q36 778 Z2 L6 Q37 779 Z2 L6 Q38 780 Z2 L6 Q39 781 Z2 L7 Q1 782 Z2 L7 Q2 783 Z2 L7 Q3 784 Z2 L7 Q4 785 Z2 L7 Q5 786 Z2 L7 Q6 787 Z2 L7 Q7 788 Z2 L7 Q8 789 Z2 L7 Q9 790 Z2 L7 Q10 791 Z2 L7 Q11 792 Z2 L7 Q12 793 Z2 L7 Q13 794 Z2 L7 Q14 795 Z2 L7 Q15 796 Z2 L7 Q16 797 Z2 L7 Q17 798 Z2 L7 Q18 799 Z2 L7 Q19 800 Z2 L7 Q20 801 Z2 L7 Q21 802 Z2 L7 Q22 803 Z2 L7 Q23 804 Z2 L7 Q24 805 Z2 L7 Q25 806 Z2 L7 Q26 807 Z2 L7 Q27 808 Z2 L7 Q28 809 Z2 L7 Q29 810 Z2 L7 Q30 811 Z2 L7 Q31 812 Z2 L7 Q32 813 Z2 L7 Q33 814 Z2 L7 Q34 815 Z2 L7 Q35 816 Z2 L7 Q36 817 Z2 L7 Q37 818 Z2 L7 Q38 819 Z2 L7 Q39 820 Z2 L8 Q1 821 Z2 L8 Q2 822 Z2 L8 Q3 823 Z2 L8 Q4 824 Z2 L8 Q5 825 Z2 L8 Q6 826 Z2 L8 Q7 827 Z2 L8 Q8 828 Z2 L8 Q9 829 Z2 L8 Q10 830 Z2 L8 Q11 831 Z2 L8 Q12 832 Z2 L8 Q13 833 Z2 L8 Q14 834 Z2 L8 Q15 835 Z2 L8 Q16 836 Z2 L8 Q17 837 Z2 L8 Q18 838 Z2 L8 Q19 839 Z2 L8 Q20 840 Z2 L8 Q21 841 Z2 L8 Q22 842 Z2 L8 Q23 843 Z2 L8 Q24 844 Z2 L8 Q25 845 Z2 L8 Q26 846 Z2 L8 Q27 847 Z2 L8 Q28 848 Z2 L8 Q29 849 Z2 L8 Q30 850 Z2 L8 Q31 851 Z2 L8 Q32 852 Z2 L8 Q33 853 Z2 L8 Q34 854 Z2 L8 Q35 855 Z2 L8 Q36 856 Z2 L8 Q37 857 Z2 L8 Q38 858 Z2 L8 Q39 859 Z2 L9 Q1 860 Z2 L9 Q2 861 Z2 L9 Q3 862 Z2 L9 Q4 863 Z2 L9 Q5 864 Z2 L9 Q6 865 Z2 L9 Q7 886 Z2 L9 Q8 887 Z2 L9 Q9 868 Z2 L9 Q10 869 Z2 L9 Q11 870 Z2 L9 Q12 871 Z2 L9 Q13 872 Z2 L9 Q14 873 Z2 L9 Q15 874 Z2 L9 Q16 875 Z2 L9 Q17 876 Z2 L9 Q18 877 Z2 L9 Q19 878 Z2 L9 Q20 879 Z2 L9 Q21 880 Z2 L9 Q22 881 Z2 L9 Q23 882 Z2 L9 Q24 883 Z2 L9 Q25 884 Z2 L9 Q26 885 Z2 L9 Q27 886 Z2 L9 Q28 887 Z2 L9 Q29 888 Z2 L9 Q30 889 Z2 L9 Q31 890 Z2 L9 Q32 891 Z2 L9 Q33 892 Z2 L9 Q34 893 Z2 L9 Q35 894 Z2 L9 Q36 895 Z2 L9 Q37 896 Z2 L9 Q38 897 Z2 L9 Q39 898 Z2 L10 Q1 899 Z2 L10 Q2 900 Z2 L10 Q3 901 Z2 L10 Q4 902 Z2 L10 Q5 903 Z2 L10 Q6 904 Z2 L10 Q7 905 Z2 L10 Q8 906 Z2 L10 Q9 907 Z2 L10 Q10 908 Z2 L10 Q11 909 Z2 L10 Q12 910 Z2 L10 Q13 911 Z2 L10 Q14 912 Z2 L10 Q15 913 Z2 L10 Q16 914 Z2 L10 Q17 915 Z2 L10 Q18 916 Z2 L10 Q19 917 Z2 L10 Q20 918 Z2 L10 Q21 919 Z2 L10 Q22 920 Z2 L10 Q23 921 Z2 L10 Q24 922 Z2 L10 Q25 923 Z2 L10 Q26 924 Z2 L10 Q27 925 Z2 L10 Q28 926 Z2 L10 Q29 927 Z2 L10 Q30 928 Z2 L10 Q31 929 Z2 L10 Q32 930 Z2 L10 Q33 931 Z2 L10 Q34 932 Z2 L10 Q35 933 Z2 L10 Q36 934 Z2 L10 Q37 935 Z2 L10 Q38 936 Z2 L10 Q39 937 Z2 L11 Q1 938 Z2 L11 Q2 939 Z2 L11 Q3 940 Z2 L11 Q4 941 Z2 L11 Q5 942 Z2 L11 Q6 943 Z2 L11 Q7 944 Z2 L11 Q8 945 Z2 L11 Q9 946 Z2 L11 Q10 947 Z2 L11 Q11 948 Z2 L11 Q12 949 Z2 L11 Q13 950 Z2 L11 Q14 951 Z2 L11 Q15 952 Z2 L11 Q16 953 Z2 L11 Q17 954 Z2 L11 Q18 955 Z2 L11 Q19 956 Z2 L11 Q20 957 Z2 L11 Q21 958 Z2 L11 Q22 959 Z2 L11 Q23 960 Z2 L11 Q24 961 Z2 L11 Q25 962 Z2 L11 Q26 963 Z2 L11 Q27 964 Z2 L11 Q28 965 Z2 L11 Q29 966 Z2 L11 Q30 967 Z2 L11 Q31 968 Z2 L11 Q32 969 Z2 L11 Q33 970 Z2 L11 Q34 971 Z2 L11 Q35 972 Z2 L11 Q36 973 Z2 L11 Q37 974 Z2 L11 Q38 975 Z2 L11 Q39 976 Z2 L12 Q1 977 Z2 L12 Q2 978 Z2 L12 Q3 979 Z2 L12 Q4 980 Z2 L12 Q5 981 Z2 L12 Q6 982 Z2 L12 Q7 983 Z2 L12 Q8 984 Z2 L12 Q9 985 Z2 L12 Q10 986 Z2 L12 Q11 987 Z2 L12 Q12 988 Z2 L12 Q13 989 Z2 L12 Q14 990 Z2 L12 Q15 991 Z2 L12 Q16 992 Z2 L12 Q17 993 Z2 L12 Q18 994 Z2 L12 Q19 985 Z2 L12 Q20 996 Z2 L12 Q21 997 Z2 L12 Q22 998 Z2 L12 Q23 999 Z2 L12 Q24 1000 Z2 L12 Q25 1001 Z2 L12 Q26 1002 Z2 L12 Q27 1003 Z2 L12 Q28 1004 Z2 L12 Q29 1005 Z2 L12 Q30 1006 Z2 L12 Q31 1007 Z2 L12 Q32 1008 Z2 L12 Q33 1009 Z2 L12 Q34 1010 Z2 L12 Q35 1011 Z2 L12 Q36 1012 Z2 L12 Q37 1013 Z2 L12 Q38 1014 Z2 L12 Q39 1015 Z2 L13 Q1 1016 Z2 L13 Q2 1017 Z2 L13 Q3 1018 Z2 L13 Q4 1019 Z2 L13 Q5 1020 Z2 L13 Q6 1021 Z2 L13 Q7 1022 Z2 L13 Q8 1023 Z2 L13 Q9 1024 Z2 L13 Q10 1025 Z2 L13 Q11 1026 Z2 L13 Q12 1027 Z2 L13 Q13 1028 Z2 L13 Q14 1029 Z2 L13 Q15 1030 Z2 L13 Q16 1031 Z2 L13 Q17 1032 Z2 L13 Q18 1033 Z2 L13 Q19 1034 Z2 L13 Q20 1035 Z2 L13 Q21 1036 Z2 L13 Q22 1037 Z2 L13 Q23 1038 Z2 L13 Q24 1039 Z2 L13 Q25 1040 Z2 L13 Q26 1041 Z2 L13 Q27 1042 Z2 L13 Q28 1043 Z2 L13 Q29 1044 Z2 L13 Q30 1045 Z2 L13 Q31 1046 Z2 L13 Q32 1047 Z2 L13 Q33 1048 Z2 L13 Q34 1048 Z2 L13 Q35 1050 Z2 L13 Q36 1051 Z2 L13 Q37 1052 Z2 L13 Q38 1053 Z2 L13 Q39 1054 Z2 L14 Q1 1055 Z2 L14 Q2 1056 Z2 L14 Q3 1057 Z2 L14 Q4 1058 Z2 L14 Q5 1059 Z2 L14 Q6 1060 Z2 L14 Q7 1061 Z2 L14 Q8 1062 Z2 L14 Q9 1063 Z2 L14 Q10 1064 Z2 L14 Q11 1065 Z2 L14 Q12 1066 Z2 L14 Q13 1067 Z2 L14 Q14 1068 Z2 L14 Q15 1069 Z2 L14 Q16 1070 Z2 L14 Q17 1071 Z2 L14 Q18 1072 Z2 L14 Q19 1073 Z2 L14 Q20 1074 Z2 L14 Q21 1075 Z2 L14 Q22 1076 Z2 L14 Q23 1077 Z2 L14 Q24 1078 Z2 L14 Q25 1079 Z2 L14 Q26 1080 Z2 L14 Q27 1081 Z2 L14 Q28 1082 Z2 L14 Q29 1083 Z2 L14 Q30 1084 Z2 L14 Q31 1085 Z2 L14 Q32 1086 Z2 L14 Q33 1087 Z2 L14 Q34 1088 Z2 L14 Q35 1089 Z2 L14 Q36 1090 Z2 L14 Q37 1091 Z2 L14 Q38 1092 Z2 L14 Q39 1093 Z3 L1 Q1 1094 Z3 L1 Q2 1095 Z3 L1 Q3 1096 Z3 L1 Q4 1097 Z3 L1 Q5 1098 Z3 L1 Q6 1099 Z3 L1 Q7 1100 Z3 L1 Q8 1101 Z3 L1 Q9 1102 Z3 L1 Q10 1103 Z3 L1 Q11 1104 Z3 L1 Q12 1105 Z3 L1 Q13 1106 Z3 L1 Q14 1107 Z3 L1 Q15 1108 Z3 L1 Q16 1109 Z3 L1 Q17 1110 Z3 L1 Q18 1111 Z3 L1 Q19 1112 Z3 L1 Q20 1113 Z3 L1 Q21 1114 Z3 L1 Q22 1115 Z3 L1 Q23 1116 Z3 L1 Q24 1117 Z3 L1 Q25 1118 Z3 L1 Q26 1119 Z3 L1 Q27 1120 Z3 L1 Q28 1121 Z3 L1 Q29 1122 Z3 L1 Q30 1123 Z3 L1 Q31 1124 Z3 L1 Q32 1125 Z3 L1 Q33 1126 Z3 L1 Q34 1127 Z3 L1 Q35 1128 Z3 L1 Q36 1129 Z3 L1 Q37 1130 Z3 L1 Q38 1131 Z3 L1 Q39 1132 Z3 L2 Q1 1133 Z3 L2 Q2 1134 Z3 L2 Q3 1135 Z3 L2 Q4 1136 Z3 L2 Q5 1137 Z3 L2 Q6 1138 Z3 L2 Q7 1139 Z3 L2 Q8 1140 Z3 L2 Q9 1141 Z3 L2 Q10 1142 Z3 L2 Q11 1143 Z3 L2 Q12 1144 Z3 L2 Q13 1145 Z3 L2 Q14 1146 Z3 L2 Q15 1147 Z3 L2 Q16 1148 Z3 L2 Q17 1149 Z3 L2 Q18 1150 Z3 L2 Q19 1151 Z3 L2 Q20 1152 Z3 L2 Q21 1153 Z3 L2 Q22 1154 Z3 L2 Q23 1155 Z3 L2 Q24 1156 Z3 L2 Q25 1157 Z3 L2 Q26 1158 Z3 L2 Q27 1159 Z3 L2 Q28 1160 Z3 L2 Q29 1161 Z3 L2 Q30 1162 Z3 L2 Q31 1163 Z3 L2 Q32 1164 Z3 L2 Q33 1165 Z3 L2 Q34 1166 Z3 L2 Q35 1167 Z3 L2 Q36 1168 Z3 L2 Q37 1169 Z3 L2 Q38 1170 Z3 L2 Q39 1171 Z3 L3 Q1 1172 Z3 L3 Q2 1173 Z3 L3 Q3 1174 Z3 L3 Q4 1175 Z3 L3 Q5 1176 Z3 L3 Q6 1177 Z3 L3 Q7 1178 Z3 L3 Q8 1179 Z3 L3 Q9 1180 Z3 L3 Q10 1181 Z3 L3 Q11 1182 Z3 L3 Q12 1183 Z3 L3 Q13 1184 Z3 L3 Q14 1185 Z3 L3 Q15 1186 Z3 L3 Q16 1187 Z3 L3 Q17 1188 Z3 L3 Q18 1189 Z3 L3 Q19 1190 Z3 L3 Q20 1191 Z3 L3 Q21 1192 Z3 L3 Q22 1193 Z3 L3 Q23 1194 Z3 L3 Q24 1195 Z3 L3 Q25 1196 Z3 L3 Q26 1197 Z3 L3 Q27 1198 Z3 L3 Q28 1199 Z3 L3 Q29 1200 Z3 L3 Q30 1201 Z3 L3 Q31 1202 Z3 L3 Q32 1203 Z3 L3 Q33 1204 Z3 L3 Q34 1205 Z3 L3 Q35 1206 Z3 L3 Q36 1207 Z3 L3 Q37 1208 Z3 L3 Q38 1209 Z3 L3 Q39 1210 Z3 L4 Q1 1211 Z3 L4 Q2 1212 Z3 L4 Q3 1213 Z3 L4 Q4 1214 Z3 L4 Q5 1215 Z3 L4 Q6 1216 Z3 L4 Q7 1217 Z3 L4 Q8 1218 Z3 L4 Q9 1219 Z3 L4 Q10 1220 Z3 L4 Q11 1221 Z3 L4 Q12 1222 Z3 L4 Q13 1223 Z3 L4 Q14 1224 Z3 L4 Q15 1225 Z3 L4 Q16 1226 Z3 L4 Q17 1227 Z3 L4 Q18 1228 Z3 L4 Q19 1229 Z3 L4 Q20 1230 Z3 L4 Q21 1231 Z3 L4 Q22 1232 Z3 L4 Q23 1233 Z3 L4 Q24 1234 Z3 L4 Q25 1235 Z3 L4 Q26 1236 Z3 L4 Q27 1237 Z3 L4 Q28 1238 Z3 L4 Q29 1239 Z3 L4 Q30 1240 Z3 L4 Q31 1241 Z3 L4 Q32 1242 Z3 L4 Q33 1243 Z3 L4 Q34 1244 Z3 L4 Q35 1245 Z3 L4 Q36 1246 Z3 L4 Q37 1247 Z3 L4 Q38 1248 Z3 L4 Q39 1249 Z3 L5 Q1 1250 Z3 L5 Q2 1251 Z3 L5 Q3 1252 Z3 L5 Q4 1253 Z3 L5 Q5 1254 Z3 L5 Q6 1255 Z3 L5 Q7 1256 Z3 L5 Q8 1257 Z3 L5 Q9 1258 Z3 L5 Q10 1259 Z3 L5 Q11 1260 Z3 L5 Q12 1261 Z3 L5 Q13 1262 Z3 L5 Q14 1263 Z3 L5 Q15 1264 Z3 L5 Q16 1265 Z3 L5 Q17 1266 Z3 L5 Q18 1267 Z3 L5 Q19 1268 Z3 L5 Q20 1269 Z3 L5 Q21 1270 Z3 L5 Q22 1271 Z3 L5 Q23 1272 Z3 L5 Q24 1273 Z3 L5 Q25 1274 Z3 L5 Q26 1275 Z3 L5 Q27 1276 Z3 L5 Q28 1277 Z3 L5 Q29 1278 Z3 L5 Q30 1279 Z3 L5 Q31 1280 Z3 L5 Q32 1281 Z3 L5 Q33 1282 Z3 L5 Q34 1283 Z3 L5 Q35 1284 Z3 L5 Q36 1285 Z3 L5 Q37 1286 Z3 L5 Q38 1287 Z3 L5 Q39 1288 Z3 L6 Q1 1289 Z3 L6 Q2 1290 Z3 L6 Q3 1291 Z3 L6 Q4 1292 Z3 L6 Q5 1293 Z3 L6 Q6 1294 Z3 L6 Q7 1295 Z3 L6 Q8 1296 Z3 L6 Q9 1297 Z3 L6 Q10 1298 Z3 L6 Q11 1299 Z3 L6 Q12 1300 Z3 L6 Q13 1301 Z3 L6 Q14 1302 Z3 L6 Q15 1303 Z3 L6 Q16 1304 Z3 L6 Q17 1305 Z3 L6 Q18 1306 Z3 L6 Q19 1307 Z3 L6 Q20 1308 Z3 L6 Q21 1309 Z3 L6 Q22 1310 Z3 L6 Q23 1311 Z3 L6 Q24 1312 Z3 L6 Q25 1313 Z3 L6 Q26 1314 Z3 L6 Q27 1315 Z3 L6 Q28 1316 Z3 L6 Q29 1317 Z3 L6 Q30 1318 Z3 L6 Q31 1319 Z3 L6 Q32 1320 Z3 L6 Q33 1321 Z3 L6 Q34 1322 Z3 L6 Q35 1323 Z3 L6 Q36 1324 Z3 L6 Q37 1325 Z3 L6 Q38 1326 Z3 L6 Q39 1327 Z3 L7 Q1 1328 Z3 L7 Q2 1329 Z3 L7 Q3 1330 Z3 L7 Q4 1331 Z3 L7 Q5 1332 Z3 L7 Q6 1333 Z3 L7 Q7 1334 Z3 L7 Q8 1335 Z3 L7 Q9 1336 Z3 L7 Q10 1337 Z3 L7 Q11 1338 Z3 L7 Q12 1339 Z3 L7 Q13 1340 Z3 L7 Q14 1341 Z3 L7 Q15 1342 Z3 L7 Q16 1343 Z3 L7 Q17 1344 Z3 L7 Q18 1345 Z3 L7 Q19 1346 Z3 L7 Q20 1347 Z3 L7 Q21 1348 Z3 L7 Q22 1349 Z3 L7 Q23 1350 Z3 L7 Q24 1351 Z3 L7 Q25 1352 Z3 L7 Q26 1353 Z3 L7 Q27 1354 Z3 L7 Q28 1355 Z3 L7 Q29 1356 Z3 L7 Q30 1357 Z3 L7 Q31 1358 Z3 L7 Q32 1359 Z3 L7 Q33 1360 Z3 L7 Q34 1361 Z3 L7 Q35 1362 Z3 L7 Q36 1363 Z3 L7 Q37 1364 Z3 L7 Q38 1365 Z3 L7 Q39 1366 Z3 L8 Q1 1367 Z3 L8 Q2 1368 Z3 L8 Q3 1369 Z3 L8 Q4 1370 Z3 L8 Q5 1371 Z3 L8 Q6 1372 Z3 L8 Q7 1373 Z3 L8 Q8 1374 Z3 L8 Q9 1375 Z3 L8 Q10 1376 Z3 L8 Q11 1377 Z3 L8 Q12 1378 Z3 L8 Q13 1379 Z3 L8 Q14 1380 Z3 L8 Q15 1381 Z3 L8 Q16 1382 Z3 L8 Q17 1383 Z3 L8 Q18 1384 Z3 L8 Q19 1385 Z3 L8 Q20 1386 Z3 L8 Q21 1387 Z3 L8 Q22 1388 Z3 L8 Q23 1389 Z3 L8 Q24 1390 Z3 L8 Q25 1391 Z3 L8 Q26 1392 Z3 L8 Q27 1393 Z3 L8 Q28 1394 Z3 L8 Q29 1395 Z3 L8 Q30 1396 Z3 L8 Q31 1397 Z3 L8 Q32 1398 Z3 L8 Q33 1399 Z3 L8 Q34 1400 Z3 L8 Q35 1401 Z3 L8 Q36 1402 Z3 L8 Q37 1403 Z3 L8 Q38 1404 Z3 L8 Q39 1405 Z3 L9 Q1 1406 Z3 L9 Q2 1407 Z3 L9 Q3 1408 Z3 L9 Q4 1409 Z3 L9 Q5 1410 Z3 L9 Q6 1411 Z3 L9 Q7 1412 Z3 L9 Q8 1413 Z3 L9 Q9 1414 Z3 L9 Q10 1415 Z3 L9 Q11 1416 Z3 L9 Q12 1417 Z3 L9 Q13 1418 Z3 L9 Q14 1418 Z3 L9 Q15 1420 Z3 L9 Q16 1421 Z3 L9 Q17 1422 Z3 L9 Q18 1423 Z3 L9 Q19 1424 Z3 L9 Q20 1425 Z3 L9 Q21 1426 Z3 L9 Q22 1427 Z3 L9 Q23 1428 Z3 L9 Q24 1429 Z3 L9 Q25 1430 Z3 L9 Q26 1431 Z3 L9 Q27 1432 Z3 L9 Q28 1433 Z3 L9 Q29 1434 Z3 L9 Q30 1435 Z3 L9 Q31 1436 Z3 L9 Q32 1437 Z3 L9 Q33 1438 Z3 L9 Q34 1439 Z3 L9 Q35 1440 Z3 L9 Q36 1441 Z3 L9 Q37 1442 Z3 L9 Q38 1443 Z3 L9 Q39 1444 Z3 L10 Q1 1445 Z3 L10 Q2 1446 Z3 L10 Q3 1447 Z3 L10 Q4 1448 Z3 L10 Q5 1449 Z3 L10 Q6 1450 Z3 L10 Q7 1451 Z3 L10 Q8 1452 Z3 L10 Q9 1453 Z3 L10 Q10 1454 Z3 L10 Q11 1455 Z3 L10 Q12 1456 Z3 L10 Q13 1457 Z3 L10 Q14 1458 Z3 L10 Q15 1459 Z3 L10 Q16 1460 Z3 L10 Q17 1461 Z3 L10 Q18 1462 Z3 L10 Q19 1463 Z3 L10 Q20 1464 Z3 L10 Q21 1465 Z3 L10 Q22 1466 Z3 L10 Q23 1467 Z3 L10 Q24 1468 Z3 L10 Q25 1469 Z3 L10 Q26 1470 Z3 L10 Q27 1471 Z3 L10 Q28 1472 Z3 L10 Q29 1473 Z3 L10 Q30 1474 Z3 L10 Q31 1475 Z3 L10 Q32 1476 Z3 L10 Q33 1477 Z3 L10 Q34 1478 Z3 L10 Q35 1479 Z3 L10 Q36 1480 Z3 L10 Q37 1481 Z3 L10 Q38 1482 Z3 L10 Q39 1483 Z3 L11 Q1 1484 Z3 L11 Q2 1485 Z3 L11 Q3 1486 Z3 L11 Q4 1487 Z3 L11 Q5 1488 Z3 L11 Q6 1489 Z3 L11 Q7 1490 Z3 L11 Q8 1491 Z3 L11 Q9 1492 Z3 L11 Q10 1493 Z3 L11 Q11 1494 Z3 L11 Q12 1495 Z3 L11 Q13 1496 Z3 L11 Q14 1497 Z3 L11 Q15 1498 Z3 L11 Q16 1499 Z3 L11 Q17 1500 Z3 L11 Q18 1501 Z3 L11 Q19 1502 Z3 L11 Q20 1503 Z3 L11 Q21 1504 Z3 L11 Q22 1505 Z3 L11 Q23 1506 Z3 L11 Q24 1507 Z3 L11 Q25 1508 Z3 L11 Q26 1509 Z3 L11 Q27 1510 Z3 L11 Q28 1511 Z3 L11 Q29 1512 Z3 L11 Q30 1513 Z3 L11 Q31 1514 Z3 L11 Q32 1515 Z3 L11 Q33 1516 Z3 L11 Q34 1517 Z3 L11 Q35 1518 Z3 L11 Q36 1519 Z3 L11 Q37 1520 Z3 L11 Q38 1521 Z3 L11 Q39 1522 Z3 L12 Q1 1523 Z3 L12 Q2 1524 Z3 L12 Q3 1525 Z3 L12 Q4 1526 Z3 L12 Q5 1527 Z3 L12 Q6 1528 Z3 L12 Q7 1529 Z3 L12 Q8 1530 Z3 L12 Q9 1531 Z3 L12 Q10 1532 Z3 L12 Q11 1533 Z3 L12 Q12 1534 Z3 L12 Q13 1535 Z3 L12 Q14 1536 Z3 L12 Q15 1537 Z3 L12 Q16 1538 Z3 L12 Q17 1539 Z3 L12 Q18 1540 Z3 L12 Q19 1541 Z3 L12 Q20 1542 Z3 L12 Q21 1543 Z3 L12 Q22 1544 Z3 L12 Q23 1545 Z3 L12 Q24 1546 Z3 L12 Q25 1547 Z3 L12 Q26 1548 Z3 L12 Q27 1549 Z3 L12 Q28 1550 Z3 L12 Q29 1551 Z3 L12 Q30 1552 Z3 L12 Q31 1553 Z3 L12 Q32 1554 Z3 L12 Q33 1555 Z3 L12 Q34 1556 Z3 L12 Q35 1557 Z3 L12 Q36 1558 Z3 L12 Q37 1559 Z3 L12 Q38 1560 Z3 L12 Q39 1561 Z3 L13 Q1 1562 Z3 L13 Q2 1563 Z3 L13 Q3 1564 Z3 L13 Q4 1565 Z3 L13 Q5 1566 Z3 L13 Q6 1567 Z3 L13 Q7 1568 Z3 L13 Q8 1569 Z3 L13 Q9 1570 Z3 L13 Q10 1571 Z3 L13 Q11 1572 Z3 L13 Q12 1573 Z3 L13 Q13 1574 Z3 L13 Q14 1575 Z3 L13 Q15 1576 Z3 L13 Q16 1577 Z3 L13 Q17 1578 Z3 L13 Q18 1579 Z3 L13 Q19 1580 Z3 L13 Q20 1581 Z3 L13 Q21 1582 Z3 L13 Q22 1583 Z3 L13 Q23 1584 Z3 L13 Q24 1585 Z3 L13 Q25 1586 Z3 L13 Q26 1587 Z3 L13 Q27 1588 Z3 L13 Q28 1589 Z3 L13 Q29 1590 Z3 L13 Q30 1591 Z3 L13 Q31 1592 Z3 L13 Q32 1593 Z3 L13 Q33 1594 Z3 L13 Q34 1595 Z3 L13 Q35 1596 Z3 L13 Q36 1597 Z3 L13 Q37 1598 Z3 L13 Q38 1599 Z3 L13 Q39 1600 Z3 L14 Q1 1601 Z3 L14 Q2 1602 Z3 L14 Q3 1603 Z3 L14 Q4 1604 Z3 L14 Q5 1605 Z3 L14 Q6 1606 Z3 L14 Q7 1607 Z3 L14 Q8 1608 Z3 L14 Q9 1609 Z3 L14 Q10 1610 Z3 L14 Q11 1611 Z3 L14 Q12 1612 Z3 L14 Q13 1613 Z3 L14 Q14 1614 Z3 L14 Q15 1615 Z3 L14 Q16 1616 Z3 L14 Q17 1617 Z3 L14 Q18 1618 Z3 L14 Q19 1619 Z3 L14 Q20 1620 Z3 L14 Q21 1621 Z3 L14 Q22 1622 Z3 L14 Q23 1623 Z3 L14 Q24 1624 Z3 L14 Q25 1625 Z3 L14 Q26 1626 Z3 L14 Q27 1627 Z3 L14 Q28 1628 Z3 L14 Q29 1629 Z3 L14 Q30 1630 Z3 L14 Q31 1631 Z3 L14 Q32 1632 Z3 L14 Q33 1633 Z3 L14 Q34 1634 Z3 L14 Q35 1635 Z3 L14 Q36 1636 Z3 L14 Q37 1637 Z3 L14 Q38 1638 Z3 L14 Q39 1639 Z4 L1 Q1 1640 Z4 L1 Q2 1641 Z4 L1 Q3 1642 Z4 L1 Q4 1643 Z4 L1 Q5 1644 Z4 L1 Q6 1645 Z4 L1 Q7 1646 Z4 L1 Q8 1647 Z4 L1 Q9 1648 Z4 L1 Q10 1649 Z4 L1 Q11 1650 Z4 L1 Q12 1651 Z4 L1 Q13 1652 Z4 L1 Q14 1653 Z4 L1 Q15 1654 Z4 L1 Q16 1655 Z4 L1 Q17 1656 Z4 L1 Q18 1657 Z4 L1 Q19 1658 Z4 L1 Q20 1659 Z4 L1 Q21 1660 Z4 L1 Q22 1661 Z4 L1 Q23 1662 Z4 L1 Q24 1663 Z4 L1 Q25 1664 Z4 L1 Q26 1665 Z4 L1 Q27 1666 Z4 L1 Q28 1667 Z4 L1 Q29 1668 Z4 L1 Q30 1669 Z4 L1 Q31 1670 Z4 L1 Q32 1671 Z4 L1 Q33 1672 Z4 L1 Q34 1673 Z4 L1 Q35 1674 Z4 L1 Q36 1675 Z4 L1 Q37 1676 Z4 L1 Q38 1677 Z4 L1 Q39 1678 Z4 L2 Q1 1679 Z4 L2 Q2 1680 Z4 L2 Q3 1681 Z4 L2 Q4 1682 Z4 L2 Q5 1683 Z4 L2 Q6 1684 Z4 L2 Q7 1685 Z4 L2 Q8 1686 Z4 L2 Q9 1687 Z4 L2 Q10 1688 Z4 L2 Q11 1689 Z4 L2 Q12 1690 Z4 L2 Q13 1691 Z4 L2 Q14 1692 Z4 L2 Q15 1693 Z4 L2 Q16 1694 Z4 L2 Q17 1695 Z4 L2 Q18 1696 Z4 L2 Q19 1697 Z4 L2 Q20 1698 Z4 L2 Q21 1699 Z4 L2 Q22 1700 Z4 L2 Q23 1701 Z4 L2 Q24 1702 Z4 L2 Q25 1703 Z4 L2 Q26 1704 Z4 L2 Q27 1705 Z4 L2 Q28 1706 Z4 L2 Q29 1707 Z4 L2 Q30 1708 Z4 L2 Q31 1709 Z4 L2 Q32 1710 Z4 L2 Q33 1711 Z4 L2 Q34 1712 Z4 L2 Q35 1713 Z4 L2 Q36 1714 Z4 L2 Q37 1715 Z4 L2 Q38 1716 Z4 L2 Q39 1717 Z4 L3 Q1 1718 Z4 L3 Q2 1719 Z4 L3 Q3 1720 Z4 L3 Q4 1721 Z4 L3 Q5 1722 Z4 L3 Q6 1723 Z4 L3 Q7 1724 Z4 L3 Q8 1725 Z4 L3 Q9 1726 Z4 L3 Q10 1727 Z4 L3 Q11 1728 Z4 L3 Q12 1729 Z4 L3 Q13 1730 Z4 L3 Q14 1731 Z4 L3 Q15 1732 Z4 L3 Q16 1733 Z4 L3 Q17 1734 Z4 L3 Q18 1735 Z4 L3 Q19 1736 Z4 L3 Q20 1737 Z4 L3 Q21 1738 Z4 L3 Q22 1739 Z4 L3 Q23 1740 Z4 L3 Q24 1741 Z4 L3 Q25 1742 Z4 L3 Q26 1743 Z4 L3 Q27 1744 Z4 L3 Q28 1745 Z4 L3 Q29 1746 Z4 L3 Q30 1747 Z4 L3 Q31 1748 Z4 L3 Q32 1749 Z4 L3 Q33 1750 Z4 L3 Q34 1751 Z4 L3 Q35 1752 Z4 L3 Q36 1753 Z4 L3 Q37 1754 Z4 L3 Q38 1755 Z4 L3 Q39 1756 Z4 L4 Q1 1757 Z4 L4 Q2 1758 Z4 L4 Q3 1759 Z4 L4 Q4 1760 Z4 L4 Q5 1761 Z4 L4 Q6 1762 Z4 L4 Q7 1763 Z4 L4 Q8 1764 Z4 L4 Q9 1765 Z4 L4 Q10 1766 Z4 L4 Q11 1767 Z4 L4 Q12 1768 Z4 L4 Q13 1769 Z4 L4 Q14 1770 Z4 L4 Q15 1771 Z4 L4 Q16 1772 Z4 L4 Q17 1773 Z4 L4 Q18 1774 Z4 L4 Q19 1775 Z4 L4 Q20 1776 Z4 L4 Q21 1777 Z4 L4 Q22 1778 Z4 L4 Q23 1779 Z4 L4 Q24 1780 Z4 L4 Q25 1781 Z4 L4 Q26 1782 Z4 L4 Q27 1783 Z4 L4 Q28 1784 Z4 L4 Q29 1785 Z4 L4 Q30 1786 Z4 L4 Q31 1787 Z4 L4 Q32 1788 Z4 L4 Q33 1789 Z4 L4 Q34 1790 Z4 L4 Q35 1791 Z4 L4 Q36 1792 Z4 L4 Q37 1793 Z4 L4 Q38 1794 Z4 L4 Q39 1795 Z4 L5 Q1 1796 Z4 L5 Q2 1797 Z4 L5 Q3 1798 Z4 L5 Q4 1799 Z4 L5 Q5 1800 Z4 L5 Q6 1801 Z4 L5 Q7 1802 Z4 L5 Q8 1803 Z4 L5 Q9 1804 Z4 L5 Q10 1805 Z4 L5 Q11 1806 Z4 L5 Q12 1807 Z4 L5 Q13 1808 Z4 L5 Q14 1809 Z4 L5 Q15 1810 Z4 L5 Q16 1811 Z4 L5 Q17 1812 Z4 L5 Q18 1813 Z4 L5 Q19 1814 Z4 L5 Q20 1815 Z4 L5 Q21 1816 Z4 L5 Q22 1817 Z4 L5 Q23 1818 Z4 L5 Q24 1819 Z4 L5 Q25 1820 Z4 L5 Q26 1821 Z4 L5 Q27 1822 Z4 L5 Q28 1823 Z4 L5 Q29 1824 Z4 L5 Q30 1825 Z4 L5 Q31 1826 Z4 L5 Q32 1827 Z4 L5 Q33 1828 Z4 L5 Q34 1829 Z4 L5 Q35 1830 Z4 L5 Q36 1831 Z4 L5 Q37 1832 Z4 L5 Q38 1833 Z4 L5 Q39 1834 Z4 L6 Q1 1835 Z4 L6 Q2 1836 Z4 L6 Q3 1837 Z4 L6 Q4 1838 Z4 L6 Q5 1839 Z4 L6 Q6 1840 Z4 L6 Q7 1841 Z4 L6 Q8 1842 Z4 L6 Q9 1843 Z4 L6 Q10 1844 Z4 L6 Q11 1845 Z4 L6 Q12 1846 Z4 L6 Q13 1847 Z4 L6 Q14 1848 Z4 L6 Q15 1849 Z4 L6 Q16 1850 Z4 L6 Q17 1851 Z4 L6 Q18 1852 Z4 L6 Q19 1853 Z4 L6 Q20 1854 Z4 L6 Q21 1855 Z4 L6 Q22 1856 Z4 L6 Q23 1857 Z4 L6 Q24 1858 Z4 L6 Q25 1859 Z4 L6 Q26 1860 Z4 L6 Q27 1861 Z4 L6 Q28 1862 Z4 L6 Q29 1863 Z4 L6 Q30 1864 Z4 L6 Q31 1865 Z4 L6 Q32 1866 Z4 L6 Q33 1867 Z4 L6 Q34 1868 Z4 L6 Q35 1869 Z4 L6 Q36 1870 Z4 L6 Q37 1871 Z4 L6 Q38 1872 Z4 L6 Q39 1873 Z4 L7 Q1 1874 Z4 L7 Q2 1875 Z4 L7 Q3 1876 Z4 L7 Q4 1877 Z4 L7 Q5 1878 Z4 L7 Q6 1879 Z4 L7 Q7 1880 Z4 L7 Q8 1881 Z4 L7 Q9 1882 Z4 L7 Q10 1883 Z4 L7 Q11 1884 Z4 L7 Q12 1885 Z4 L7 Q13 1886 Z4 L7 Q14 1887 Z4 L7 Q15 1888 Z4 L7 Q16 1889 Z4 L7 Q17 1890 Z4 L7 Q18 1891 Z4 L7 Q19 1892 Z4 L7 Q20 1893 Z4 L7 Q21 1894 Z4 L7 Q22 1895 Z4 L7 Q23 1896 Z4 L7 Q24 1897 Z4 L7 Q25 1898 Z4 L7 Q26 1899 Z4 L7 Q27 1900 Z4 L7 Q28 1901 Z4 L7 Q29 1902 Z4 L7 Q30 1903 Z4 L7 Q31 1904 Z4 L7 Q32 1905 Z4 L7 Q33 1906 Z4 L7 Q34 1907 Z4 L7 Q35 1908 Z4 L7 Q36 1909 Z4 L7 Q37 1910 Z4 L7 Q38 1911 Z4 L7 Q39 1912 Z4 L8 Q1 1913 Z4 L8 Q2 1914 Z4 L8 Q3 1915 Z4 L8 Q4 1916 Z4 L8 Q5 1917 Z4 L8 Q6 1918 Z4 L8 Q7 1919 Z4 L8 Q8 1920 Z4 L8 Q9 1921 Z4 L8 Q10 1922 Z4 L8 Q11 1923 Z4 L8 Q12 1924 Z4 L8 Q13 1925 Z4 L8 Q14 1926 Z4 L8 Q15 1927 Z4 L8 Q16 1928 Z4 L8 Q17 1929 Z4 L8 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1997 Z4 L10 Q8 1998 Z4 L10 Q9 1999 Z4 L10 Q10 2000 Z4 L10 Q11 2001 Z4 L10 Q12 2002 Z4 L10 Q13 2003 Z4 L10 Q14 2004 Z4 L10 Q15 2005 Z4 L10 Q16 2006 Z4 L10 Q17 2007 Z4 L10 Q18 2008 Z4 L10 Q19 2009 Z4 L10 Q20 2010 Z4 L10 Q21 2011 Z4 L10 Q22 2012 Z4 L10 Q23 2013 Z4 L10 Q24 2014 Z4 L10 Q25 2015 Z4 L10 Q26 2016 Z4 L10 Q27 2017 Z4 L10 Q28 2018 Z4 L10 Q29 2019 Z4 L10 Q30 2020 Z4 L10 Q31 2021 Z4 L10 Q32 2022 Z4 L10 Q33 2023 Z4 L10 Q34 2024 Z4 L10 Q35 2025 Z4 L10 Q36 2026 Z4 L10 Q37 2027 Z4 L10 Q38 2028 Z4 L10 Q39 2029 Z4 L11 Q1 2030 Z4 L11 Q2 2031 Z4 L11 Q3 2032 Z4 L11 Q4 2033 Z4 L11 Q5 2034 Z4 L11 Q6 2035 Z4 L11 Q7 2036 Z4 L11 Q8 2037 Z4 L11 Q9 2038 Z4 L11 Q10 2039 Z4 L11 Q11 2040 Z4 L11 Q12 2041 Z4 L11 Q13 2042 Z4 L11 Q14 2043 Z4 L11 Q15 2044 Z4 L11 Q16 2045 Z4 L11 Q17 2046 Z4 L11 Q18 2047 Z4 L11 Q19 2048 Z4 L11 Q20 2049 Z4 L11 Q21 2050 Z4 L11 Q22 2051 Z4 L11 Q23 2052 Z4 L11 Q24 2053 Z4 L11 Q25 2054 Z4 L11 Q26 2055 Z4 L11 Q27 2056 Z4 L11 Q28 2057 Z4 L11 Q29 2058 Z4 L11 Q30 2059 Z4 L11 Q31 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2651 Z1 L8 Q58 2652 Z1 L8 Q59 2653 Z1 L8 Q60 2654 Z1 L8 Q61 2655 Z1 L8 Q62 2656 Z1 L8 Q63 2657 Z1 L8 Q64 2658 Z1 L8 Q65 2659 Z1 L8 Q66 2660 Z1 L8 Q67 2661 Z1 L8 Q68 2662 Z1 L8 Q69 2663 Z1 L8 Q70 2664 Z1 L8 Q71 2665 Z1 L8 Q72 2666 Z1 L8 Q73 2667 Z1 L8 Q74 2668 Z1 L8 Q75 2669 Z1 L8 Q76 2670 Z1 L8 Q77 2671 Z1 L8 Q78 2672 Z1 L8 Q79 2673 Z1 L8 Q80 2674 Z1 L8 Q81 2675 Z1 L8 Q82 2676 Z1 L8 Q83 2677 Z1 L8 Q84 2678 Z1 L8 Q85 2679 Z1 L8 Q86 2680 Z1 L8 Q87 2681 Z1 L8 Q88 2682 Z1 L8 Q89 2683 Z1 L8 Q90 2684 Z1 L8 Q91 2685 Z1 L8 Q92 2686 Z1 L8 Q93 2687 Z1 L8 Q94 2688 Z1 L8 Q95 2689 Z1 L8 Q96 2690 Z1 L8 Q97 2691 Z1 L8 Q98 2692 Z1 L8 Q99 2693 Z1 L8 Q100 2694 Z1 L8 Q101 2695 Z1 L8 Q102 2696 Z1 L8 Q103 2697 Z1 L9 Q40 2698 Z1 L9 Q41 2699 Z1 L9 Q42 2700 Z1 L9 Q43 2701 Z1 L9 Q44 2702 Z1 L9 Q45 2703 Z1 L9 Q46 2704 Z1 L9 Q47 2705 Z1 L9 Q48 2706 Z1 L9 Q49 2707 Z1 L9 Q50 2708 Z1 L9 Q51 2709 Z1 L9 Q52 2710 Z1 L9 Q53 2711 Z1 L9 Q54 2712 Z1 L9 Q55 2713 Z1 L9 Q56 2714 Z1 L9 Q57 2715 Z1 L9 Q58 2716 Z1 L9 Q59 2717 Z1 L9 Q60 2718 Z1 L9 Q61 2719 Z1 L9 Q62 2720 Z1 L9 Q63 2721 Z1 L9 Q64 2722 Z1 L9 Q65 2723 Z1 L9 Q66 2724 Z1 L9 Q67 2725 Z1 L9 Q68 2726 Z1 L9 Q69 2727 Z1 L9 Q70 2728 Z1 L9 Q71 2729 Z1 L9 Q72 2730 Z1 L9 Q73 2731 Z1 L9 Q74 2732 Z1 L9 Q75 2733 Z1 L9 Q76 2734 Z1 L9 Q77 2735 Z1 L9 Q78 2736 Z1 L9 Q79 2737 Z1 L9 Q80 2738 Z1 L9 Q81 2739 Z1 L9 Q82 2740 Z1 L9 Q83 2741 Z1 L9 Q84 2742 Z1 L9 Q85 2743 Z1 L9 Q86 2744 Z1 L9 Q87 2745 Z1 L9 Q88 2746 Z1 L9 Q89 2747 Z1 L9 Q90 2748 Z1 L9 Q91 2749 Z1 L9 Q92 2750 Z1 L9 Q93 2751 Z1 L9 Q94 2752 Z1 L9 Q95 2753 Z1 L9 Q96 2754 Z1 L9 Q97 2755 Z1 L9 Q98 2756 Z1 L9 Q99 2757 Z1 L9 Q100 2758 Z1 L9 Q101 2759 Z1 L9 Q102 2760 Z1 L9 Q103 2761 Z1 L10 Q40 2762 Z1 L10 Q41 2763 Z1 L10 Q42 2764 Z1 L10 Q43 2765 Z1 L10 Q44 2766 Z1 L10 Q45 2767 Z1 L10 Q46 2768 Z1 L10 Q47 2769 Z1 L10 Q48 2770 Z1 L10 Q49 2771 Z1 L10 Q50 2772 Z1 L10 Q51 2773 Z1 L10 Q52 2774 Z1 L10 Q53 2775 Z1 L10 Q54 2776 Z1 L10 Q55 2777 Z1 L10 Q56 2778 Z1 L10 Q57 2779 Z1 L10 Q58 2780 Z1 L10 Q59 2781 Z1 L10 Q60 2782 Z1 L10 Q61 2783 Z1 L10 Q62 2784 Z1 L10 Q63 2785 Z1 L10 Q64 2786 Z1 L10 Q65 2787 Z1 L10 Q66 2788 Z1 L10 Q67 2789 Z1 L10 Q68 2790 Z1 L10 Q69 2791 Z1 L10 Q70 2792 Z1 L10 Q71 2793 Z1 L10 Q72 2794 Z1 L10 Q73 2795 Z1 L10 Q74 2796 Z1 L10 Q75 2797 Z1 L10 Q76 2798 Z1 L10 Q77 2799 Z1 L10 Q78 2800 Z1 L10 Q79 2801 Z1 L10 Q80 2802 Z1 L10 Q81 2803 Z1 L10 Q82 2804 Z1 L10 Q83 2805 Z1 L10 Q84 2806 Z1 L10 Q85 2807 Z1 L10 Q86 2808 Z1 L10 Q87 2809 Z1 L10 Q88 2810 Z1 L10 Q89 2811 Z1 L10 Q90 2812 Z1 L10 Q91 2813 Z1 L10 Q92 2814 Z1 L10 Q93 2815 Z1 L10 Q94 2816 Z1 L10 Q95 2817 Z1 L10 Q96 2818 Z1 L10 Q97 2819 Z1 L10 Q98 2820 Z1 L10 Q99 2821 Z1 L10 Q100 2822 Z1 L10 Q101 2823 Z1 L10 Q102 2824 Z1 L10 Q103 2825 Z1 L11 Q40 2826 Z1 L11 Q41 2827 Z1 L11 Q42 2828 Z1 L11 Q43 2829 Z1 L11 Q44 2830 Z1 L11 Q45 2831 Z1 L11 Q46 2832 Z1 L11 Q47 2833 Z1 L11 Q48 2834 Z1 L11 Q49 2835 Z1 L11 Q50 2836 Z1 L11 Q51 2837 Z1 L11 Q52 2838 Z1 L11 Q53 2839 Z1 L11 Q54 2840 Z1 L11 Q55 2841 Z1 L11 Q56 2842 Z1 L11 Q57 2843 Z1 L11 Q58 2844 Z1 L11 Q59 2845 Z1 L11 Q60 2846 Z1 L11 Q61 2847 Z1 L11 Q62 2848 Z1 L11 Q63 2849 Z1 L11 Q64 2850 Z1 L11 Q65 2851 Z1 L11 Q66 2852 Z1 L11 Q67 2853 Z1 L11 Q68 2854 Z1 L11 Q69 2855 Z1 L11 Q70 2856 Z1 L11 Q71 2857 Z1 L11 Q72 2858 Z1 L11 Q73 2859 Z1 L11 Q74 2860 Z1 L11 Q75 2861 Z1 L11 Q76 2862 Z1 L11 Q77 2863 Z1 L11 Q78 2864 Z1 L11 Q79 2865 Z1 L11 Q80 2866 Z1 L11 Q81 2867 Z1 L11 Q82 2868 Z1 L11 Q83 2869 Z1 L11 Q84 2870 Z1 L11 Q85 2871 Z1 L11 Q86 2872 Z1 L11 Q87 2873 Z1 L11 Q88 2874 Z1 L11 Q89 2875 Z1 L11 Q90 2876 Z1 L11 Q91 2877 Z1 L11 Q92 2878 Z1 L11 Q93 2879 Z1 L11 Q94 2880 Z1 L11 Q95 2881 Z1 L11 Q96 2882 Z1 L11 Q97 2883 Z1 L11 Q98 2884 Z1 L11 Q99 2885 Z1 L11 Q100 2886 Z1 L11 Q101 2887 Z1 L11 Q102 2888 Z1 L11 Q103 2889 Z1 L12 Q40 2890 Z1 L12 Q41 2891 Z1 L12 Q42 2892 Z1 L12 Q43 2893 Z1 L12 Q44 2894 Z1 L12 Q45 2895 Z1 L12 Q46 2896 Z1 L12 Q47 2897 Z1 L12 Q48 2898 Z1 L12 Q49 2899 Z1 L12 Q50 2900 Z1 L12 Q51 2901 Z1 L12 Q52 2902 Z1 L12 Q53 2903 Z1 L12 Q54 2904 Z1 L12 Q55 2905 Z1 L12 Q56 2906 Z1 L12 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2969 Z1 L13 Q56 2970 Z1 L13 Q57 2971 Z1 L13 Q58 2972 Z1 L13 Q59 2973 Z1 L13 Q60 2974 Z1 L13 Q61 2975 Z1 L13 Q62 2976 Z1 L13 Q63 2977 Z1 L13 Q64 2978 Z1 L13 Q65 2979 Z1 L13 Q66 2980 Z1 L13 Q67 2981 Z1 L13 Q68 2982 Z1 L13 Q69 2983 Z1 L13 Q70 2984 Z1 L13 Q71 2985 Z1 L13 Q72 2986 Z1 L13 Q73 2987 Z1 L13 Q74 2988 Z1 L13 Q75 2989 Z1 L13 Q76 2990 Z1 L13 Q77 2991 Z1 L13 Q78 2992 Z1 L13 Q79 2993 Z1 L13 Q80 2994 Z1 L13 Q81 2995 Z1 L13 Q82 2996 Z1 L13 Q83 2997 Z1 L13 Q84 2998 Z1 L13 Q85 2999 Z1 L13 Q86 3000 Z1 L13 Q87 3001 Z1 L13 Q88 3002 Z1 L13 Q89 3003 Z1 L13 Q90 3004 Z1 L13 Q91 3005 Z1 L13 Q92 3006 Z1 L13 Q93 3007 Z1 L13 Q94 3008 Z1 L13 Q95 3009 Z1 L13 Q96 3010 Z1 L13 Q97 3011 Z1 L13 Q98 3012 Z1 L13 Q99 3013 Z1 L13 Q100 3014 Z1 L13 Q101 3015 Z1 L13 Q102 3016 Z1 L13 Q103 3017 Z1 L14 Q40 3018 Z1 L14 Q41 3019 Z1 L14 Q42 3020 Z1 L14 Q43 3021 Z1 L14 Q44 3022 Z1 L14 Q45 3023 Z1 L14 Q46 3024 Z1 L14 Q47 3025 Z1 L14 Q48 3026 Z1 L14 Q49 3027 Z1 L14 Q50 3028 Z1 L14 Q51 3029 Z1 L14 Q52 3030 Z1 L14 Q53 3031 Z1 L14 Q54 3032 Z1 L14 Q55 3033 Z1 L14 Q56 3034 Z1 L14 Q57 3035 Z1 L14 Q58 3036 Z1 L14 Q59 3037 Z1 L14 Q60 3038 Z1 L14 Q61 3039 Z1 L14 Q62 3040 Z1 L14 Q63 3041 Z1 L14 Q64 3042 Z1 L14 Q65 3043 Z1 L14 Q66 3044 Z1 L14 Q67 3045 Z1 L14 Q68 3046 Z1 L14 Q69 3047 Z1 L14 Q70 3048 Z1 L14 Q71 3049 Z1 L14 Q72 3050 Z1 L14 Q73 3051 Z1 L14 Q74 3052 Z1 L14 Q75 3053 Z1 L14 Q76 3054 Z1 L14 Q77 3055 Z1 L14 Q78 3056 Z1 L14 Q79 3057 Z1 L14 Q80 3058 Z1 L14 Q81 3059 Z1 L14 Q82 3060 Z1 L14 Q83 3061 Z1 L14 Q84 3062 Z1 L14 Q85 3063 Z1 L14 Q86 3064 Z1 L14 Q87 3065 Z1 L14 Q88 3066 Z1 L14 Q89 3067 Z1 L14 Q90 3068 Z1 L14 Q91 3069 Z1 L14 Q92 3070 Z1 L14 Q93 3071 Z1 L14 Q94 3072 Z1 L14 Q95 3073 Z1 L14 Q96 3074 Z1 L14 Q97 3075 Z1 L14 Q98 3076 Z1 L14 Q99 3077 Z1 L14 Q100 3078 Z1 L14 Q101 3079 Z1 L14 Q102 3080 Z1 L14 Q103 3081 Z2 L1 Q40 3082 Z2 L1 Q41 3083 Z2 L1 Q42 3084 Z2 L1 Q43 3085 Z2 L1 Q44 3086 Z2 L1 Q45 3087 Z2 L1 Q46 3088 Z2 L1 Q47 3089 Z2 L1 Q48 3090 Z2 L1 Q49 3091 Z2 L1 Q50 3092 Z2 L1 Q51 3083 Z2 L1 Q52 3094 Z2 L1 Q53 3095 Z2 L1 Q54 3096 Z2 L1 Q55 3097 Z2 L1 Q56 3098 Z2 L1 Q57 3099 Z2 L1 Q58 3100 Z2 L1 Q59 3101 Z2 L1 Q60 3102 Z2 L1 Q61 3103 Z2 L1 Q62 3104 Z2 L1 Q63 3105 Z2 L1 Q64 3106 Z2 L1 Q65 3107 Z2 L1 Q66 3108 Z2 L1 Q67 3109 Z2 L1 Q68 3110 Z2 L1 Q69 3111 Z2 L1 Q70 3112 Z2 L1 Q71 3113 Z2 L1 Q72 3114 Z2 L1 Q73 3115 Z2 L1 Q74 3116 Z2 L1 Q75 3117 Z2 L1 Q76 3118 Z2 L1 Q77 3119 Z2 L1 Q78 3120 Z2 L1 Q79 3121 Z2 L1 Q80 3122 Z2 L1 Q81 3123 Z2 L1 Q82 3124 Z2 L1 Q83 3125 Z2 L1 Q84 3126 Z2 L1 Q85 3127 Z2 L1 Q86 3128 Z2 L1 Q87 3129 Z2 L1 Q88 3130 Z2 L1 Q89 3131 Z2 L1 Q90 3132 Z2 L1 Q91 3133 Z2 L1 Q92 3134 Z2 L1 Q93 3135 Z2 L1 Q94 3136 Z2 L1 Q95 3137 Z2 L1 Q96 3138 Z2 L1 Q97 3139 Z2 L1 Q98 3140 Z2 L1 Q99 3141 Z2 L1 Q100 3142 Z2 L1 Q101 3143 Z2 L1 Q102 3144 Z2 L1 Q103 3145 Z2 L2 Q40 3146 Z2 L2 Q41 3147 Z2 L2 Q42 3148 Z2 L2 Q43 3149 Z2 L2 Q44 3150 Z2 L2 Q45 3151 Z2 L2 Q46 3152 Z2 L2 Q47 3153 Z2 L2 Q48 3154 Z2 L2 Q49 3155 Z2 L2 Q50 3156 Z2 L2 Q51 3157 Z2 L2 Q52 3158 Z2 L2 Q53 3159 Z2 L2 Q54 3160 Z2 L2 Q55 3161 Z2 L2 Q56 3162 Z2 L2 Q57 3163 Z2 L2 Q58 3164 Z2 L2 Q59 3165 Z2 L2 Q60 3166 Z2 L2 Q61 3167 Z2 L2 Q62 3168 Z2 L2 Q63 3169 Z2 L2 Q64 3170 Z2 L2 Q65 3171 Z2 L2 Q66 3172 Z2 L2 Q67 3173 Z2 L2 Q68 3174 Z2 L2 Q69 3175 Z2 L2 Q70 3176 Z2 L2 Q71 3177 Z2 L2 Q72 3178 Z2 L2 Q73 3179 Z2 L2 Q74 3180 Z2 L2 Q75 3181 Z2 L2 Q76 3182 Z2 L2 Q77 3183 Z2 L2 Q78 3184 Z2 L2 Q79 3185 Z2 L2 Q80 3186 Z2 L2 Q81 3187 Z2 L2 Q82 3188 Z2 L2 Q83 3189 Z2 L2 Q84 3190 Z2 L2 Q85 3191 Z2 L2 Q86 3192 Z2 L2 Q87 3193 Z2 L2 Q88 3194 Z2 L2 Q89 3195 Z2 L2 Q90 3196 Z2 L2 Q91 3197 Z2 L2 Q92 3198 Z2 L2 Q93 3199 Z2 L2 Q94 3200 Z2 L2 Q95 3201 Z2 L2 Q96 3202 Z2 L2 Q97 3203 Z2 L2 Q98 3204 Z2 L2 Q99 3205 Z2 L2 Q100 3206 Z2 L2 Q101 3207 Z2 L2 Q102 3208 Z2 L2 Q103 3209 Z2 L3 Q40 3210 Z2 L3 Q41 3211 Z2 L3 Q42 3212 Z2 L3 Q43 3213 Z2 L3 Q44 3214 Z2 L3 Q45 3215 Z2 L3 Q46 3216 Z2 L3 Q47 3217 Z2 L3 Q48 3218 Z2 L3 Q49 3219 Z2 L3 Q50 3220 Z2 L3 Q51 3221 Z2 L3 Q52 3222 Z2 L3 Q53 3223 Z2 L3 Q54 3224 Z2 L3 Q55 3225 Z2 L3 Q56 3226 Z2 L3 Q57 3227 Z2 L3 Q58 3228 Z2 L3 Q59 3229 Z2 L3 Q60 3230 Z2 L3 Q61 3231 Z2 L3 Q62 3232 Z2 L3 Q63 3233 Z2 L3 Q64 3234 Z2 L3 Q65 3235 Z2 L3 Q66 3236 Z2 L3 Q67 3237 Z2 L3 Q68 3238 Z2 L3 Q69 3239 Z2 L3 Q70 3240 Z2 L3 Q71 3241 Z2 L3 Q72 3242 Z2 L3 Q73 3243 Z2 L3 Q74 3244 Z2 L3 Q75 3245 Z2 L3 Q76 3246 Z2 L3 Q77 3247 Z2 L3 Q78 3248 Z2 L3 Q79 3249 Z2 L3 Q80 3250 Z2 L3 Q81 3251 Z2 L3 Q82 3252 Z2 L3 Q83 3253 Z2 L3 Q84 3254 Z2 L3 Q85 3255 Z2 L3 Q86 3256 Z2 L3 Q87 3257 Z2 L3 Q88 3258 Z2 L3 Q89 3259 Z2 L3 Q90 3260 Z2 L3 Q91 3261 Z2 L3 Q92 3262 Z2 L3 Q93 3263 Z2 L3 Q94 3264 Z2 L3 Q95 3265 Z2 L3 Q96 3266 Z2 L3 Q97 3267 Z2 L3 Q98 3268 Z2 L3 Q99 3269 Z2 L3 Q100 3270 Z2 L3 Q101 3271 Z2 L3 Q102 3272 Z2 L3 Q103 3273 Z2 L4 Q40 3274 Z2 L4 Q41 3275 Z2 L4 Q42 3276 Z2 L4 Q43 3277 Z2 L4 Q44 3278 Z2 L4 Q45 3279 Z2 L4 Q46 3280 Z2 L4 Q47 3281 Z2 L4 Q48 3282 Z2 L4 Q49 3283 Z2 L4 Q50 3284 Z2 L4 Q51 3285 Z2 L4 Q52 3286 Z2 L4 Q53 3287 Z2 L4 Q54 3288 Z2 L4 Q55 3289 Z2 L4 Q56 3290 Z2 L4 Q57 3291 Z2 L4 Q58 3292 Z2 L4 Q59 3293 Z2 L4 Q60 3294 Z2 L4 Q61 3295 Z2 L4 Q62 3296 Z2 L4 Q63 3297 Z2 L4 Q64 3298 Z2 L4 Q65 3299 Z2 L4 Q66 3300 Z2 L4 Q67 3301 Z2 L4 Q68 3302 Z2 L4 Q69 3303 Z2 L4 Q70 3304 Z2 L4 Q71 3305 Z2 L4 Q72 3306 Z2 L4 Q73 3307 Z2 L4 Q74 3308 Z2 L4 Q75 3309 Z2 L4 Q76 3310 Z2 L4 Q77 3311 Z2 L4 Q78 3312 Z2 L4 Q79 3313 Z2 L4 Q80 3314 Z2 L4 Q81 3315 Z2 L4 Q82 3316 Z2 L4 Q83 3317 Z2 L4 Q84 3318 Z2 L4 Q85 3319 Z2 L4 Q86 3320 Z2 L4 Q87 3321 Z2 L4 Q88 3322 Z2 L4 Q89 3323 Z2 L4 Q90 3324 Z2 L4 Q91 3325 Z2 L4 Q92 3326 Z2 L4 Q93 3327 Z2 L4 Q94 3328 Z2 L4 Q95 3329 Z2 L4 Q96 3330 Z2 L4 Q97 3331 Z2 L4 Q98 3332 Z2 L4 Q99 3333 Z2 L4 Q100 3334 Z2 L4 Q101 3335 Z2 L4 Q102 3336 Z2 L4 Q103 3337 Z2 L5 Q40 3338 Z2 L5 Q41 3339 Z2 L5 Q42 3340 Z2 L5 Q43 3341 Z2 L5 Q44 3342 Z2 L5 Q45 3343 Z2 L5 Q46 3344 Z2 L5 Q47 3345 Z2 L5 Q48 3346 Z2 L5 Q49 3347 Z2 L5 Q50 3348 Z2 L5 Q51 3349 Z2 L5 Q52 3350 Z2 L5 Q53 3351 Z2 L5 Q54 3352 Z2 L5 Q55 3353 Z2 L5 Q56 3354 Z2 L5 Q57 3355 Z2 L5 Q58 3356 Z2 L5 Q59 3357 Z2 L5 Q60 3358 Z2 L5 Q61 3359 Z2 L5 Q62 3360 Z2 L5 Q63 3361 Z2 L5 Q64 3362 Z2 L5 Q65 3363 Z2 L5 Q66 3364 Z2 L5 Q67 3365 Z2 L5 Q68 3366 Z2 L5 Q69 3367 Z2 L5 Q70 3368 Z2 L5 Q71 3369 Z2 L5 Q72 3370 Z2 L5 Q73 3371 Z2 L5 Q74 3372 Z2 L5 Q75 3373 Z2 L5 Q76 3374 Z2 L5 Q77 3375 Z2 L5 Q78 3376 Z2 L5 Q79 3377 Z2 L5 Q80 3378 Z2 L5 Q81 3379 Z2 L5 Q82 3380 Z2 L5 Q83 3381 Z2 L5 Q84 3382 Z2 L5 Q85 3383 Z2 L5 Q86 3384 Z2 L5 Q87 3385 Z2 L5 Q88 3386 Z2 L5 Q89 3387 Z2 L5 Q90 3388 Z2 L5 Q91 3389 Z2 L5 Q92 3390 Z2 L5 Q93 3391 Z2 L5 Q94 3392 Z2 L5 Q95 3393 Z2 L5 Q96 3394 Z2 L5 Q97 3395 Z2 L5 Q98 3396 Z2 L5 Q99 3397 Z2 L5 Q100 3398 Z2 L5 Q101 3399 Z2 L5 Q102 3400 Z2 L5 Q103 3401 Z2 L6 Q40 3402 Z2 L6 Q41 3403 Z2 L6 Q42 3404 Z2 L6 Q43 3405 Z2 L6 Q44 3406 Z2 L6 Q45 3407 Z2 L6 Q46 3408 Z2 L6 Q47 3409 Z2 L6 Q48 3410 Z2 L6 Q49 3411 Z2 L6 Q50 3412 Z2 L6 Q51 3413 Z2 L6 Q52 3414 Z2 L6 Q53 3415 Z2 L6 Q54 3416 Z2 L6 Q55 3417 Z2 L6 Q56 3418 Z2 L6 Q57 3419 Z2 L6 Q58 3420 Z2 L6 Q59 3421 Z2 L6 Q60 3422 Z2 L6 Q61 3423 Z2 L6 Q62 3424 Z2 L6 Q63 3425 Z2 L6 Q64 3426 Z2 L6 Q65 3427 Z2 L6 Q66 3428 Z2 L6 Q67 3429 Z2 L6 Q68 3430 Z2 L6 Q69 3431 Z2 L6 Q70 3432 Z2 L6 Q71 3433 Z2 L6 Q72 3434 Z2 L6 Q73 3435 Z2 L6 Q74 3436 Z2 L6 Q75 3437 Z2 L6 Q76 3438 Z2 L6 Q77 3439 Z2 L6 Q78 3440 Z2 L6 Q79 3441 Z2 L6 Q80 3442 Z2 L6 Q81 3443 Z2 L6 Q82 3444 Z2 L6 Q83 3445 Z2 L6 Q84 3446 Z2 L6 Q85 3447 Z2 L6 Q86 3448 Z2 L6 Q87 3449 Z2 L6 Q88 3450 Z2 L6 Q89 3451 Z2 L6 Q90 3452 Z2 L6 Q91 3453 Z2 L6 Q92 3454 Z2 L6 Q93 3455 Z2 L6 Q94 3456 Z2 L6 Q95 3457 Z2 L6 Q96 3458 Z2 L6 Q97 3459 Z2 L6 Q98 3460 Z2 L6 Q99 3461 Z2 L6 Q100 3462 Z2 L6 Q101 3463 Z2 L6 Q102 3464 Z2 L6 Q103 3465 Z2 L7 Q40 3466 Z2 L7 Q41 3467 Z2 L7 Q42 3468 Z2 L7 Q43 3469 Z2 L7 Q44 3470 Z2 L7 Q45 3471 Z2 L7 Q46 3472 Z2 L7 Q47 3473 Z2 L7 Q48 3474 Z2 L7 Q49 3475 Z2 L7 Q50 3476 Z2 L7 Q51 3477 Z2 L7 Q52 3478 Z2 L7 Q53 3479 Z2 L7 Q54 3480 Z2 L7 Q55 3481 Z2 L7 Q56 3482 Z2 L7 Q57 3483 Z2 L7 Q58 3484 Z2 L7 Q59 3485 Z2 L7 Q60 3486 Z2 L7 Q61 3487 Z2 L7 Q62 3488 Z2 L7 Q63 3489 Z2 L7 Q64 3490 Z2 L7 Q65 3491 Z2 L7 Q66 3492 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13963 Z4 L28 Q58 13964 Z4 L28 Q59 13965 Z4 L28 Q60 13966 Z4 L28 Q61 13967 Z4 L28 Q62 13968 Z4 L28 Q63 13969 Z4 L28 Q64 13970 Z4 L28 Q65 13971 Z4 L28 Q66 13972 Z4 L28 Q67 13973 Z4 L28 Q68 13974 Z4 L28 Q69 13975 Z4 L28 Q70 13976 Z4 L28 Q71 13977 Z4 L28 Q72 13978 Z4 L28 Q73 13979 Z4 L28 Q74 13980 Z4 L28 Q75 13981 Z4 L28 Q76 13982 Z4 L28 Q77 13983 Z4 L28 Q78 13984 Z4 L28 Q79 13985 Z4 L28 Q80 13986 Z4 L28 Q81 13987 Z4 L28 Q82 13988 Z4 L28 Q83 13989 Z4 L28 Q84 13990 Z4 L28 Q85 13991 Z4 L28 Q86 13992 Z4 L28 Q87 13993 Z4 L28 Q88 13994 Z4 L28 Q89 13995 Z4 L28 Q90 13996 Z4 L28 Q91 13997 Z4 L28 Q92 13998 Z4 L28 Q93 13999 Z4 L28 Q94 14000 Z4 L28 Q95 14001 Z4 L28 Q96 14002 Z4 L28 Q97 14003 Z4 L28 Q98 14004 Z4 L28 Q99 14005 Z4 L28 Q100 14006 Z4 L28 Q101 14007 Z4 L28 Q102 14008 Z4 L28 Q103 14009 Z4 L29 Q1 14010 Z4 L29 Q2 14011 Z4 L29 Q3 14012 Z4 L29 Q4 14013 Z4 L29 Q5 14014 Z4 L29 Q6 14015 Z4 L29 Q7 14016 Z4 L29 Q8 14017 Z4 L29 Q9 14018 Z4 L29 Q10 14019 Z4 L29 Q11 14020 Z4 L29 Q12 14021 Z4 L29 Q13 14022 Z4 L29 Q14 14023 Z4 L29 Q15 14024 Z4 L29 Q16 14025 Z4 L29 Q17 14026 Z4 L29 Q18 14027 Z4 L29 Q19 14028 Z4 L29 Q20 14029 Z4 L29 Q21 14030 Z4 L29 Q22 14031 Z4 L29 Q23 14032 Z4 L29 Q24 14033 Z4 L29 Q25 14034 Z4 L29 Q26 14035 Z4 L29 Q27 14036 Z4 L29 Q28 14037 Z4 L29 Q29 14038 Z4 L29 Q30 14039 Z4 L29 Q31 14040 Z4 L29 Q32 14041 Z4 L29 Q33 14042 Z4 L29 Q34 14043 Z4 L29 Q35 14044 Z4 L29 Q36 14045 Z4 L29 Q37 14046 Z4 L29 Q38 14047 Z4 L29 Q39 14048 Z4 L29 Q40 14049 Z4 L29 Q41 14050 Z4 L29 Q42 14051 Z4 L29 Q43 14052 Z4 L29 Q44 14053 Z4 L29 Q45 14054 Z4 L29 Q46 14055 Z4 L29 Q47 14056 Z4 L29 Q48 14057 Z4 L29 Q49 14058 Z4 L29 Q50 14059 Z4 L29 Q51 14060 Z4 L29 Q52 14061 Z4 L29 Q53 14062 Z4 L29 Q54 14063 Z4 L29 Q55 14064 Z4 L29 Q56 14065 Z4 L29 Q57 14066 Z4 L29 Q58 14067 Z4 L29 Q59 14068 Z4 L29 Q60 14069 Z4 L29 Q61 14070 Z4 L29 Q62 14071 Z4 L29 Q63 14072 Z4 L29 Q64 14073 Z4 L29 Q65 14074 Z4 L29 Q66 14075 Z4 L29 Q67 14076 Z4 L29 Q68 14077 Z4 L29 Q69 14078 Z4 L29 Q70 14079 Z4 L29 Q71 14080 Z4 L29 Q72 14081 Z4 L29 Q73 14082 Z4 L29 Q74 14083 Z4 L29 Q75 14084 Z4 L29 Q76 14085 Z4 L29 Q77 14086 Z4 L29 Q78 14087 Z4 L29 Q79 14088 Z4 L29 Q80 14089 Z4 L29 Q81 14090 Z4 L29 Q82 14091 Z4 L29 Q83 14092 Z4 L29 Q84 14093 Z4 L29 Q85 14094 Z4 L29 Q86 14095 Z4 L29 Q87 14096 Z4 L29 Q88 14097 Z4 L29 Q89 14098 Z4 L29 Q90 14099 Z4 L29 Q91 14100 Z4 L29 Q92 14101 Z4 L29 Q93 14102 Z4 L29 Q94 14103 Z4 L29 Q95 14104 Z4 L29 Q96 14105 Z4 L29 Q97 14106 Z4 L29 Q98 14107 Z4 L29 Q99 14108 Z4 L29 Q100 14109 Z4 L29 Q101 14110 Z4 L29 Q102 14111 Z4 L29 Q103 14112 Z4 L30 Q1 14113 Z4 L30 Q2 14114 Z4 L30 Q3 14115 Z4 L30 Q4 14116 Z4 L30 Q5 14117 Z4 L30 Q6 14118 Z4 L30 Q7 14119 Z4 L30 Q8 14120 Z4 L30 Q9 14121 Z4 L30 Q10 14122 Z4 L30 Q11 14123 Z4 L30 Q12 14124 Z4 L30 Q13 14125 Z4 L30 Q14 14126 Z4 L30 Q15 14127 Z4 L30 Q16 14128 Z4 L30 Q17 14129 Z4 L30 Q18 14130 Z4 L30 Q19 14131 Z4 L30 Q20 14132 Z4 L30 Q21 14133 Z4 L30 Q22 14134 Z4 L30 Q23 14135 Z4 L30 Q24 14136 Z4 L30 Q25 14137 Z4 L30 Q26 14138 Z4 L30 Q27 14139 Z4 L30 Q28 14140 Z4 L30 Q29 14141 Z4 L30 Q30 14142 Z4 L30 Q31 14143 Z4 L30 Q32 14144 Z4 L30 Q33 14145 Z4 L30 Q34 14146 Z4 L30 Q35 14147 Z4 L30 Q36 14148 Z4 L30 Q37 14149 Z4 L30 Q38 14150 Z4 L30 Q39 14151 Z4 L30 Q40 14152 Z4 L30 Q41 14153 Z4 L30 Q42 14154 Z4 L30 Q43 14155 Z4 L30 Q44 14156 Z4 L30 Q45 14157 Z4 L30 Q46 14158 Z4 L30 Q47 14159 Z4 L30 Q48 14160 Z4 L30 Q49 14161 Z4 L30 Q50 14162 Z4 L30 Q51 14163 Z4 L30 Q52 14164 Z4 L30 Q53 14165 Z4 L30 Q54 14166 Z4 L30 Q55 14167 Z4 L30 Q56 14168 Z4 L30 Q57 14169 Z4 L30 Q58 14170 Z4 L30 Q59 14171 Z4 L30 Q60 14172 Z4 L30 Q61 14173 Z4 L30 Q62 14174 Z4 L30 Q63 14175 Z4 L30 Q64 14176 Z4 L30 Q65 14177 Z4 L30 Q66 14178 Z4 L30 Q67 14179 Z4 L30 Q68 14180 Z4 L30 Q69 14181 Z4 L30 Q70 14182 Z4 L30 Q71 14183 Z4 L30 Q72 14184 Z4 L30 Q73 14185 Z4 L30 Q74 14186 Z4 L30 Q75 14187 Z4 L30 Q76 14188 Z4 L30 Q77 14189 Z4 L30 Q78 14190 Z4 L30 Q79 14191 Z4 L30 Q80 14192 Z4 L30 Q81 14193 Z4 L30 Q82 14194 Z4 L30 Q83 14195 Z4 L30 Q84 14196 Z4 L30 Q85 14197 Z4 L30 Q86 14198 Z4 L30 Q87 14199 Z4 L30 Q88 14200 Z4 L30 Q89 14201 Z4 L30 Q90 14202 Z4 L30 Q91 14203 Z4 L30 Q92 14204 Z4 L30 Q93 14205 Z4 L30 Q94 14206 Z4 L30 Q95 14207 Z4 L30 Q96 14208 Z4 L30 Q97 14209 Z4 L30 Q98 14210 Z4 L30 Q99 14211 Z4 L30 Q100 14212 Z4 L30 Q101 14213 Z4 L30 Q102 14214 Z4 L30 Q103 14215 Z4 L31 Q1 14216 Z4 L31 Q2 14217 Z4 L31 Q3 14218 Z4 L31 Q4 14219 Z4 L31 Q5 14220 Z4 L31 Q6 14221 Z4 L31 Q7 14222 Z4 L31 Q8 14223 Z4 L31 Q9 14224 Z4 L31 Q10 14225 Z4 L31 Q11 14226 Z4 L31 Q12 14227 Z4 L31 Q13 14228 Z4 L31 Q14 14229 Z4 L31 Q15 14230 Z4 L31 Q16 14231 Z4 L31 Q17 14232 Z4 L31 Q18 14233 Z4 L31 Q19 14234 Z4 L31 Q20 14235 Z4 L31 Q21 14236 Z4 L31 Q22 14237 Z4 L31 Q23 14238 Z4 L31 Q24 14239 Z4 L31 Q25 14240 Z4 L31 Q26 14241 Z4 L31 Q27 14242 Z4 L31 Q28 14243 Z4 L31 Q29 14244 Z4 L31 Q30 14245 Z4 L31 Q31 14246 Z4 L31 Q32 14247 Z4 L31 Q33 14248 Z4 L31 Q34 14249 Z4 L31 Q35 14250 Z4 L31 Q36 14251 Z4 L31 Q37 14252 Z4 L31 Q38 14253 Z4 L31 Q39 14254 Z4 L31 Q40 14255 Z4 L31 Q41 14256 Z4 L31 Q42 14257 Z4 L31 Q43 14258 Z4 L31 Q44 14259 Z4 L31 Q45 14260 Z4 L31 Q46 14261 Z4 L31 Q47 14262 Z4 L31 Q48 14263 Z4 L31 Q49 14264 Z4 L31 Q50 14265 Z4 L31 Q51 14266 Z4 L31 Q52 14267 Z4 L31 Q53 14268 Z4 L31 Q54 14269 Z4 L31 Q55 14270 Z4 L31 Q56 14271 Z4 L31 Q57 14272 Z4 L31 Q58 14273 Z4 L31 Q59 14274 Z4 L31 Q60 14275 Z4 L31 Q61 14276 Z4 L31 Q62 14277 Z4 L31 Q63 14278 Z4 L31 Q64 14279 Z4 L31 Q65 14280 Z4 L31 Q66 14281 Z4 L31 Q67 14282 Z4 L31 Q68 14283 Z4 L31 Q69 14284 Z4 L31 Q70 14285 Z4 L31 Q71 14286 Z4 L31 Q72 14287 Z4 L31 Q73 14288 Z4 L31 Q74 14289 Z4 L31 Q75 14290 Z4 L31 Q76 14291 Z4 L31 Q77 14292 Z4 L31 Q78 14293 Z4 L31 Q79 14294 Z4 L31 Q80 14295 Z4 L31 Q81 14296 Z4 L31 Q82 14297 Z4 L31 Q83 14298 Z4 L31 Q84 14299 Z4 L31 Q85 14300 Z4 L31 Q86 14301 Z4 L31 Q87 14302 Z4 L31 Q88 14303 Z4 L31 Q89 14304 Z4 L31 Q90 14305 Z4 L31 Q91 14306 Z4 L31 Q92 14307 Z4 L31 Q93 14308 Z4 L31 Q94 14309 Z4 L31 Q95 14310 Z4 L31 Q96 14311 Z4 L31 Q97 14312 Z4 L31 Q98 14313 Z4 L31 Q99 14314 Z4 L31 Q100 14315 Z4 L31 Q101 14316 Z4 L31 Q102 14317 Z4 L31 Q103 14318 Z4 L32 Q1 14319 Z4 L32 Q2 14320 Z4 L32 Q3 14321 Z4 L32 Q4 14322 Z4 L32 Q5 14323 Z4 L32 Q6 14324 Z4 L32 Q7 14325 Z4 L32 Q8 14326 Z4 L32 Q9 14327 Z4 L32 Q10 14328 Z4 L32 Q11 14329 Z4 L32 Q12 14330 Z4 L32 Q13 14331 Z4 L32 Q14 14332 Z4 L32 Q15 14333 Z4 L32 Q16 14334 Z4 L32 Q17 14335 Z4 L32 Q18 14336 Z4 L32 Q19 14337 Z4 L32 Q20 14338 Z4 L32 Q21 14339 Z4 L32 Q22 14340 Z4 L32 Q23 14341 Z4 L32 Q24 14342 Z4 L32 Q25 14343 Z4 L32 Q26 14344 Z4 L32 Q27 14345 Z4 L32 Q28 14346 Z4 L32 Q29 14347 Z4 L32 Q30 14348 Z4 L32 Q31 14349 Z4 L32 Q32 14350 Z4 L32 Q33 14351 Z4 L32 Q34 14352 Z4 L32 Q35 14353 Z4 L32 Q36 14354 Z4 L32 Q37 14355 Z4 L32 Q38 14356 Z4 L32 Q39 14357 Z4 L32 Q40 14358 Z4 L32 Q41 14359 Z4 L32 Q42 14360 Z4 L32 Q43 14361 Z4 L32 Q44 14362 Z4 L32 Q45 14363 Z4 L32 Q46 14364 Z4 L32 Q47 14365 Z4 L32 Q48 14366 Z4 L32 Q49 14367 Z4 L32 Q50 14368 Z4 L32 Q51 14369 Z4 L32 Q52 14370 Z4 L32 Q53 14371 Z4 L32 Q54 14372 Z4 L32 Q55 14373 Z4 L32 Q56 14374 Z4 L32 Q57 14375 Z4 L32 Q58 14376 Z4 L32 Q59 14377 Z4 L32 Q60 14378 Z4 L32 Q61 14379 Z4 L32 Q62 14380 Z4 L32 Q63 14381 Z4 L32 Q64 14382 Z4 L32 Q65 14383 Z4 L32 Q66 14384 Z4 L32 Q67 14385 Z4 L32 Q68 14386 Z4 L32 Q69 14387 Z4 L32 Q70 14388 Z4 L32 Q71 14389 Z4 L32 Q72 14390 Z4 L32 Q73 14391 Z4 L32 Q74 14392 Z4 L32 Q75 14393 Z4 L32 Q76 14394 Z4 L32 Q77 14395 Z4 L32 Q78 14396 Z4 L32 Q79 14397 Z4 L32 Q80 14398 Z4 L32 Q81 14399 Z4 L32 Q82 14400 Z4 L32 Q83 14401 Z4 L32 Q84 14402 Z4 L32 Q85 14403 Z4 L32 Q86 14404 Z4 L32 Q87 14405 Z4 L32 Q88 14406 Z4 L32 Q89 14407 Z4 L32 Q90 14408 Z4 L32 Q91 14409 Z4 L32 Q92 14410 Z4 L32 Q93 14411 Z4 L32 Q94 14412 Z4 L32 Q95 14413 Z4 L32 Q96 14414 Z4 L32 Q97 14415 Z4 L32 Q98 14416 Z4 L32 Q99 14417 Z4 L32 Q100 14418 Z4 L32 Q101 14419 Z4 L32 Q102 14420 Z4 L32 Q103 14421 Z4 L33 Q1 14422 Z4 L33 Q2 14423 Z4 L33 Q3 14424 Z4 L33 Q4 14425 Z4 L33 Q5 14426 Z4 L33 Q6 14427 Z4 L33 Q7 14428 Z4 L33 Q8 14429 Z4 L33 Q9 14430 Z4 L33 Q10 14431 Z4 L33 Q11 14432 Z4 L33 Q12 14433 Z4 L33 Q13 14434 Z4 L33 Q14 14435 Z4 L33 Q15 14436 Z4 L33 Q16 14437 Z4 L33 Q17 14438 Z4 L33 Q18 14439 Z4 L33 Q19 14440 Z4 L33 Q20 14441 Z4 L33 Q21 14442 Z4 L33 Q22 14443 Z4 L33 Q23 14444 Z4 L33 Q24 14445 Z4 L33 Q25 14446 Z4 L33 Q26 14447 Z4 L33 Q27 14448 Z4 L33 Q28 14449 Z4 L33 Q29 14450 Z4 L33 Q30 14451 Z4 L33 Q31 14452 Z4 L33 Q32 14453 Z4 L33 Q33 14454 Z4 L33 Q34 14455 Z4 L33 Q35 14456 Z4 L33 Q36 14457 Z4 L33 Q37 14458 Z4 L33 Q38 14459 Z4 L33 Q39 14460 Z4 L33 Q40 14461 Z4 L33 Q41 14462 Z4 L33 Q42 14463 Z4 L33 Q43 14464 Z4 L33 Q44 14465 Z4 L33 Q45 14466 Z4 L33 Q46 14467 Z4 L33 Q47 14468 Z4 L33 Q48 14469 Z4 L33 Q49 14470 Z4 L33 Q50 14471 Z4 L33 Q51 14472 Z4 L33 Q52 14473 Z4 L33 Q53 14474 Z4 L33 Q54 14475 Z4 L33 Q55 14476 Z4 L33 Q56 14477 Z4 L33 Q57 14478 Z4 L33 Q58 14479 Z4 L33 Q59 14480 Z4 L33 Q60 14481 Z4 L33 Q61 14482 Z4 L33 Q62 14483 Z4 L33 Q63 14484 Z4 L33 Q64 14485 Z4 L33 Q65 14486 Z4 L33 Q66 14487 Z4 L33 Q67 14488 Z4 L33 Q68 14489 Z4 L33 Q69 14490 Z4 L33 Q70 14491 Z4 L33 Q71 14492 Z4 L33 Q72 14493 Z4 L33 Q73 14494 Z4 L33 Q74 14495 Z4 L33 Q75 14496 Z4 L33 Q76 14497 Z4 L33 Q77 14498 Z4 L33 Q78 14499 Z4 L33 Q79 14500 Z4 L33 Q80 14501 Z4 L33 Q81 14502 Z4 L33 Q82 14503 Z4 L33 Q83 14504 Z4 L33 Q84 14505 Z4 L33 Q85 14506 Z4 L33 Q86 14507 Z4 L33 Q87 14508 Z4 L33 Q88 14509 Z4 L33 Q89 14510 Z4 L33 Q90 14511 Z4 L33 Q91 14512 Z4 L33 Q92 14513 Z4 L33 Q93 14514 Z4 L33 Q94 14515 Z4 L33 Q95 14516 Z4 L33 Q96 14517 Z4 L33 Q97 14518 Z4 L33 Q98 14519 Z4 L33 Q99 14520 Z4 L33 Q100 14521 Z4 L33 Q101 14522 Z4 L33 Q102 14523 Z4 L33 Q103 14524 Z4 L34 Q1 14525 Z4 L34 Q2 14526 Z4 L34 Q3 14527 Z4 L34 Q4 14528 Z4 L34 Q5 14529 Z4 L34 Q6 14530 Z4 L34 Q7 14531 Z4 L34 Q8 14532 Z4 L34 Q9 14533 Z4 L34 Q10 14534 Z4 L34 Q11 14535 Z4 L34 Q12 14536 Z4 L34 Q13 14537 Z4 L34 Q14 14538 Z4 L34 Q15 14539 Z4 L34 Q16 14540 Z4 L34 Q17 14541 Z4 L34 Q18 14542 Z4 L34 Q19 14543 Z4 L34 Q20 14544 Z4 L34 Q21 14545 Z4 L34 Q22 14546 Z4 L34 Q23 14547 Z4 L34 Q24 14548 Z4 L34 Q25 14549 Z4 L34 Q26 14550 Z4 L34 Q27 14551 Z4 L34 Q28 14552 Z4 L34 Q29 14553 Z4 L34 Q30 14554 Z4 L34 Q31 14555 Z4 L34 Q32 14556 Z4 L34 Q33 14557 Z4 L34 Q34 14558 Z4 L34 Q35 14559 Z4 L34 Q36 14560 Z4 L34 Q37 14561 Z4 L34 Q38 14562 Z4 L34 Q39 14563 Z4 L34 Q40 14564 Z4 L34 Q41 14565 Z4 L34 Q42 14566 Z4 L34 Q43 14567 Z4 L34 Q44 14568 Z4 L34 Q45 14569 Z4 L34 Q46 14570 Z4 L34 Q47 14571 Z4 L34 Q48 14572 Z4 L34 Q49 14573 Z4 L34 Q50 14574 Z4 L34 Q51 14575 Z4 L34 Q52 14576 Z4 L34 Q53 14577 Z4 L34 Q54 14578 Z4 L34 Q55 14579 Z4 L34 Q56 14580 Z4 L34 Q57 14581 Z4 L34 Q58 14582 Z4 L34 Q59 14583 Z4 L34 Q60 14584 Z4 L34 Q61 14585 Z4 L34 Q62 14586 Z4 L34 Q63 14587 Z4 L34 Q64 14588 Z4 L34 Q65 14589 Z4 L34 Q66 14590 Z4 L34 Q67 14591 Z4 L34 Q68 14592 Z4 L34 Q69 14593 Z4 L34 Q70 14594 Z4 L34 Q71 14595 Z4 L34 Q72 14596 Z4 L34 Q73 14597 Z4 L34 Q74 14598 Z4 L34 Q75 14599 Z4 L34 Q76 14600 Z4 L34 Q77 14601 Z4 L34 Q78 14602 Z4 L34 Q79 14603 Z4 L34 Q80 14604 Z4 L34 Q81 14605 Z4 L34 Q82 14606 Z4 L34 Q83 14607 Z4 L34 Q84 14608 Z4 L34 Q85 14609 Z4 L34 Q86 14610 Z4 L34 Q87 14611 Z4 L34 Q88 14612 Z4 L34 Q89 14613 Z4 L34 Q90 14614 Z4 L34 Q91 14615 Z4 L34 Q92 14616 Z4 L34 Q93 14617 Z4 L34 Q94 14618 Z4 L34 Q95 14619 Z4 L34 Q96 14620 Z4 L34 Q97 14621 Z4 L34 Q98 14622 Z4 L34 Q99 14623 Z4 L34 Q100 14624 Z4 L34 Q101 14625 Z4 L34 Q102 14626 Z4 L34 Q103 14627 Z4 L35 Q1 14628 Z4 L35 Q2 14629 Z4 L35 Q3 14630 Z4 L35 Q4 14631 Z4 L35 Q5 14632 Z4 L35 Q6 14633 Z4 L35 Q7 14634 Z4 L35 Q8 14635 Z4 L35 Q9 14636 Z4 L35 Q10 14637 Z4 L35 Q11 14638 Z4 L35 Q12 14639 Z4 L35 Q13 14640 Z4 L35 Q14 14641 Z4 L35 Q15 14642 Z4 L35 Q16 14643 Z4 L35 Q17 14644 Z4 L35 Q18 14645 Z4 L35 Q19 14646 Z4 L35 Q20 14647 Z4 L35 Q21 14648 Z4 L35 Q22 14649 Z4 L35 Q23 14650 Z4 L35 Q24 14651 Z4 L35 Q25 14652 Z4 L35 Q26 14653 Z4 L35 Q27 14654 Z4 L35 Q28 14655 Z4 L35 Q29 14656 Z4 L35 Q30 14657 Z4 L35 Q31 14658 Z4 L35 Q32 14659 Z4 L35 Q33 14660 Z4 L35 Q34 14661 Z4 L35 Q35 14662 Z4 L35 Q36 14663 Z4 L35 Q37 14664 Z4 L35 Q38 14665 Z4 L35 Q39 14666 Z4 L35 Q40 14667 Z4 L35 Q41 14668 Z4 L35 Q42 14669 Z4 L35 Q43 14670 Z4 L35 Q44 14671 Z4 L35 Q45 14672 Z4 L35 Q46 14673 Z4 L35 Q47 14674 Z4 L35 Q48 14675 Z4 L35 Q49 14676 Z4 L35 Q50 14677 Z4 L35 Q51 14678 Z4 L35 Q52 14679 Z4 L35 Q53 14680 Z4 L35 Q54 14681 Z4 L35 Q55 14682 Z4 L35 Q56 14683 Z4 L35 Q57 14684 Z4 L35 Q58 14685 Z4 L35 Q59 14686 Z4 L35 Q60 14687 Z4 L35 Q61 14688 Z4 L35 Q62 14689 Z4 L35 Q63 14690 Z4 L35 Q64 14691 Z4 L35 Q65 14692 Z4 L35 Q66 14693 Z4 L35 Q67 14694 Z4 L35 Q68 14695 Z4 L35 Q69 14696 Z4 L35 Q70 14697 Z4 L35 Q71 14698 Z4 L35 Q72 14699 Z4 L35 Q73 14700 Z4 L35 Q74 14701 Z4 L35 Q75 14702 Z4 L35 Q76 14703 Z4 L35 Q77 14704 Z4 L35 Q78 14705 Z4 L35 Q79 14706 Z4 L35 Q80 14707 Z4 L35 Q81 14708 Z4 L35 Q82 14709 Z4 L35 Q83 14710 Z4 L35 Q84 14711 Z4 L35 Q85 14712 Z4 L35 Q86 14713 Z4 L35 Q87 14714 Z4 L35 Q88 14715 Z4 L35 Q89 14716 Z4 L35 Q90 14717 Z4 L35 Q91 14718 Z4 L35 Q92 14719 Z4 L35 Q93 14720 Z4 L35 Q94 14721 Z4 L35 Q95 14722 Z4 L35 Q96 14723 Z4 L35 Q97 14724 Z4 L35 Q98 14725 Z4 L35 Q99 14726 Z4 L35 Q100 14727 Z4 L35 Q101 14728 Z4 L35 Q102 14729 Z4 L35 Q103 14730 Z4 L36 Q1 14731 Z4 L36 Q2 14732 Z4 L36 Q3 14733 Z4 L36 Q4 14734 Z4 L36 Q5 14735 Z4 L36 Q6 14736 Z4 L36 Q7 14737 Z4 L36 Q8 14738 Z4 L36 Q9 14739 Z4 L36 Q10 14740 Z4 L36 Q11 14741 Z4 L36 Q12 14742 Z4 L36 Q13 14743 Z4 L36 Q14 14744 Z4 L36 Q15 14745 Z4 L36 Q16 14746 Z4 L36 Q17 14747 Z4 L36 Q18 14748 Z4 L36 Q19 14749 Z4 L36 Q20 14750 Z4 L36 Q21 14751 Z4 L36 Q22 14752 Z4 L36 Q23 14753 Z4 L36 Q24 14754 Z4 L36 Q25 14755 Z4 L36 Q26 14756 Z4 L36 Q27 14757 Z4 L36 Q28 14758 Z4 L36 Q29 14759 Z4 L36 Q30 14760 Z4 L36 Q31 14761 Z4 L36 Q32 14762 Z4 L36 Q33 14763 Z4 L36 Q34 14764 Z4 L36 Q35 14765 Z4 L36 Q36 14766 Z4 L36 Q37 14767 Z4 L36 Q38 14768 Z4 L36 Q39 14769 Z4 L36 Q40 14770 Z4 L36 Q41 14771 Z4 L36 Q42 14772 Z4 L36 Q43 14773 Z4 L36 Q44 14774 Z4 L36 Q45 14775 Z4 L36 Q46 14776 Z4 L36 Q47 14777 Z4 L36 Q48 14778 Z4 L36 Q49 14779 Z4 L36 Q50 14780 Z4 L36 Q51 14781 Z4 L36 Q52 14782 Z4 L36 Q53 14783 Z4 L36 Q54 14784 Z4 L36 Q55 14785 Z4 L36 Q56 14786 Z4 L36 Q57 14787 Z4 L36 Q58 14788 Z4 L36 Q59 14789 Z4 L36 Q60 14790 Z4 L36 Q61 14791 Z4 L36 Q62 14792 Z4 L36 Q63 14793 Z4 L36 Q64 14794 Z4 L36 Q65 14795 Z4 L36 Q66 14796 Z4 L36 Q67 14797 Z4 L36 Q68 14798 Z4 L36 Q69 14799 Z4 L36 Q70 14800 Z4 L36 Q71 14801 Z4 L36 Q72 14802 Z4 L36 Q73 14803 Z4 L36 Q74 14804 Z4 L36 Q75 14805 Z4 L36 Q76 14806 Z4 L36 Q77 14807 Z4 L36 Q78 14808 Z4 L36 Q79 14809 Z4 L36 Q80 14810 Z4 L36 Q81 14811 Z4 L36 Q82 14812 Z4 L36 Q83 14813 Z4 L36 Q84 14814 Z4 L36 Q85 14815 Z4 L36 Q86 14816 Z4 L36 Q87 14817 Z4 L36 Q88 14818 Z4 L36 Q89 14819 Z4 L36 Q90 14820 Z4 L36 Q91 14821 Z4 L36 Q92 14822 Z4 L36 Q93 14823 Z4 L36 Q94 14824 Z4 L36 Q95 14825 Z4 L36 Q96 14826 Z4 L36 Q97 14827 Z4 L36 Q98 14828 Z4 L36 Q99 14829 Z4 L36 Q100 14830 Z4 L36 Q101 14831 Z4 L36 Q102 14832 Z4 L36 Q103

A specific example of another embodiment of the compound of the invention includes a compound represented by formula (11):

or a pharmaceutically acceptable salt thereof, wherein Z, L¹, L², X, R¹, R², R³, and R⁴ are the same as the definitions herein, R^(G) is a hydroxyl group, a thiol group, or —NHR^(a1), and R^(a1) is the same as the definition herein.

A specific example of another embodiment of the compound of the invention includes a compound represented by formula (12):

or a pharmaceutically acceptable salt thereof, wherein X, R¹, R², R³, and R⁴ are the same as the definitions herein, R^(G) is a hydroxyl group, a thiol group, or —NHR^(a1), and R^(a1) is the same as the definition herein. A compound of formula (12) is in an interchangeable relationship with, and thus can be biologically equivalent with, a compound of formula (1a) or (3a) due to an equilibrium reaction in an aqueous solution or in the body.

A specific example of another embodiment of the compound of the invention includes a compound represented by formula (13):

or a pharmaceutically acceptable salt thereof, wherein X, Y, ring A, L³, L⁴, R¹, R², R⁴, and R⁵ are the same as the definitions herein, R^(P) is a hydroxyl group, a thiol group, or —NHR^(a1), and R^(a1) is the same as the definition herein.

A specific example of a preferred embodiment of the compound of the invention includes a compound represented by formula (14):

or a pharmaceutically acceptable salt thereof, wherein X, L³, L⁴, m, n, and R⁵ are the same as the definitions herein, R^(G) is a hydroxyl group, a thiol group, or —NHR^(a1), and R^(a1) is the same as the definition herein.

The compound of the invention is described further hereinafter.

The compound of the invention can have, depending on the type of substituent, a tautomer, stereoisomers such as geometric isomer, and enantiomer, which are encompassed by the present invention. Specifically, if the compound of the invention has one or more asymmetric carbon atoms, there is a diastereomer or an enantiomer, where a mixture of such a diastereomer or enantiomer or isolated diastereomer or enantiomer are also encompassed by the compound of the invention.

The compound of the invention can also have a structure represented by the following formula (11) due to an equilibrium state or the like, depending on the environment conditions such as temperature or humidity, or a physical factor in a solid, liquid, solution, or the like. The compound of the invention also encompasses compounds with such a structure.

In formula (11), X represents a hydroxyl group, a thiol group, or —NHRR^(a1), Z, L¹, L², R^(G), R¹, R², R³, R⁴, and R^(a1) are defined the same as the definitions herein, and formula (1a) is defined the same as the definition herein.

For example, the structures of the compounds in the Examples herein are based on estimation considered the most appropriate by those skilled in the art using proton nuclear magnetic resonance spectrum (¹H-NMR), liquid chromatography mass spectrometry (LCMS), or the like, but the structures are just estimates under each specific measurement environment. In particular, the structure of formula (1a), the structure of formula (1b), and the structure of formula (11) are possibly converted to each other or partially converted to one of the structures and mixed due to a property unique to each compound, various environmental conditions such as temperature or humidity, or physical factor in a solid, liquid, solution or the like.

The compound of the invention also includes various hydrates, solvates, and crystalline polymorphisms.

Furthermore, the compound of the invention may be substituted with an isotope (e.g., ²H (or D), ³H (or T), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ³⁵S, ¹⁸F, ¹²⁵I, or the like). Such compounds are also encompassed by the compound of the invention.

Prodrugs of the compound of the invention are also within the scope of the invention. As used herein, a prodrug refers to a derivative that results in the compound of formula (1a), (1b), or (11) by acid hydrolysis or enzymatic degradation in the body. If, for example, the compound of formula (1a), (1b), or (11) has a hydroxyl group, amino group, or carboxyl group, these groups can be modified in accordance with a conventional method to manufacture a prodrug.

Examples for a compound with a carboxy group include compounds whose carboxyl group has been converted to an alkoxycarbonyl group, alkylthiocarbonyl group, or alkylaminocarbonyl group.

Examples for a compound with an amino group include compounds whose amino group has been substituted with an alkanoyl group to be converted to an alkanoylamino group, substituted with an alkoxycarbonyl group to be converted to an alkoxycarbonylamino group, modified to an alkanoyloxymethylamino group, or converted to a hydroxylamine.

Examples for a compound with a hydroxyl group include compounds whose hydroxyl group has been substituted with the alkanoyl group described above to be converted to an alkanoyloxy group, converted to a phosphate ester, or converted to an alkanoyloxymethyloxy group.

Examples of the alkyl moiety of a group used in producing these prodrugs include the alkyl group described above. The alkyl group is optionally substituted with, for example, an alkoxy group or the like. Preferred examples thereof include the following.

Examples of compounds whose carboxyl group has been converted to an alkoxycarbonyl group include alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl, and alkoxycarbonyl substituted with an alkoxy group such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, and pivaloyloxymethoxycarbonyl.

As used herein, “pharmaceutically acceptable salt” refers to an acid addition salt or base addition salt which is pharmaceutically acceptable for use. Examples of “pharmaceutically acceptable salts” include, but are not limited to, acid addition salts such as acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, para-toluenesulfonate (tosylate), laurylsulfate, malate, ascorbate, mandelate, saccharinate, xinafoate, pamoate, cinnamate, adipate, cysteine salt, N-acetyl cysteine salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as morpholine and piperidine; amino acid addition salts wherein the amino acid is aspartic acid or glutamic acid; and the like.

The compounds of the invention can be administered directly, or as a formulation, medicament, or a pharmaceutical composition using a suitable dosage form, by oral or parenteral administration. Specific examples of such dosage forms include, but are not limited to, tablets, capsules, powder, granules, liquid agents, suspension, injections, patches, poultice, and the like. These formulations can be manufactured by a known method using an additive that is commonly used as a pharmaceutical additive.

As these additives, an excipient, disintegrant, binding agent, fluidizer, lubricant, coating agent, solubilizing agent, solubilization promotor, thickener, dispersant, stabilizer, sweetener, flavoring agent, or the like can be used depending on the objective. Specific examples of these additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like.

The dosage of the compound of the invention is appropriately selected depending on the animal targeted for administration, route of administration, disease, patient's age, body weight, and symptom. For example, the dosage is 0.01 mg as the lower limit (preferably 100 mg) and 10000 mg as the upper limit (preferably 6000 mg) per day for adults for oral administration. This amount can be administered once daily, or divided into several doses.

The compound of the invention is a compound with inhibitory activity against β-lactamase. Thus, the compound can be a prophylactic or therapeutic agent that is useful for a bacterial infection by combined use with an antimicrobial agent. Specific examples of such bacterial infections include sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, an odontogenic infection, and the like.

The compound of the invention can be used in combination with at least one agent selected from an antimicrobial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent for treating one or more bacterial infections described herein. The agent is preferably an antimicrobial agent, and more preferably a β-lactam agent. Specific examples thereof include amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefaulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442. The timing of dosing of the compound of the invention and therapeutic agents thereof is not limited. The compound and therapeutic agent can be administered concurrently or sequentially to a subject being administered therewith. The compound of the invention and the therapeutic agents can be formulated as a combined agent. The dosage of the therapeutic agent can be appropriately selected based on the clinically used dose. The ratio of the compound of the invention and the therapeutic agents can be appropriately selected depending on the subject of administration, route of administration, target disease, symptom, combination, or the like.

In another embodiment, the compound of the invention can be combined and administered concomitantly or administered at different times upon use of a pharmaceutical composition comprising an antimicrobial agent such as a β-lactam agent. Such a pharmaceutical composition comprising α-lactam agent is also within the scope of the invention, and can be used for treating or preventing a bacterial infection such as sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.

Such a medicament, formulation, or pharmaceutical composition can be manufactured by mixing the compound of the invention and/or an addition agent (e.g., antimicrobial agent such as a β-lactam agent) with any suitable component, together or separately, as a combined agent or as separate agents using any technology that is known in the art. An appropriate formulation such as a tablet, capsule, powder, granule, liquid agent, suspension, injection, patch, or poultice can be formulated by using any technology that is known in the art. If the compound of the invention and/or an addition agent (e.g., antimicrobial agent such as a β-lactam agent) are prepared as separate agents, they can be provided as a kit of two agents. The kit can provide one of the components as a single agent, with instructions (package insert or the like) instructing to combine and administer the other component (for the compound of the invention, the additional agent (e.g., antimicrobial agent such as a p-lactam agent); for the addition agent (e.g., antimicrobial agent such as a β-lactam agent), the compound of the invention) concurrently or at different times.

If the compound of the invention is used as an active ingredient of a medicament, the compound can be intended for use in not just humans, but also animals other than humans (cat, dog, cow, chicken, fish, and the like).

Hereinafter, the method of manufacturing the compound of the invention is described with examples, but the present invention is not limited thereto.

The compound of the invention can be manufactured by, for example, the manufacturing methods described below, but the methods are not limited to such methods. These manufacturing methods can be appropriately improved upon based on the expertise of those skilled in the art of organic synthetic chemistry. Salts of the compounds used as a starting material can be used in the manufacturing method described below, as long as the reaction is not affected.

In the manufacturing methods described below, even if use of a protecting group is not specifically described, a functional group other than those at the reaction point can be protected as needed and deprotected after the completion of a reaction or after a series of reactions to obtain a compound of interest if one of the functional groups other than those at the reaction point is altered under the reaction condition or if it is unsuitable for post-reaction processing. Common protecting groups described in the document (T. W. Greene and P. G. M. Wuts, “Protective Group in Organic Synthesis”, 3^(rd) Ed., John Wiley and Sons, Inc., New York (1999)) or the like can be used as the protecting groups used in these processes. A protecting group can be introduced or removed by a method that is commonly used in organic synthetic chemistry (e.g., method described in the aforementioned document or the like) or a method in accordance therewith.

The starting material and intermediate in the manufacturing methods described below can be purchased as a commercially available product or are available by synthesis in accordance with a method described in a known document or a known method from a known compound. Salts of the starting material and intermediate can also be used, as long as the reaction is not affected.

The intermediate and compound of interest in the manufacturing methods described below can also be converted into another compound encompassed by the present invention by appropriately converting their functional groups. A functional group can be converted, in doing so, by a method that is commonly used in organic synthetic chemistry (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) or a method in accordance therewith.

An inert solvent in the manufacturing methods described below refers to a solvent that does not react with starting materials, reagents, bases, acids, catalysts, ligands, or the like used in a reaction (hereinafter, also referred to as “starting materials or the like used in a reaction”). A solvent used in each step can be used as an inert solvent even if the solvent reacts with the starting materials or the like used in the reaction, as long as the reaction of interest proceeds to result in a compound of interest.

Manufacturing Method 1

The compound of formula (1a), which is represented by formula (1-7) can be manufactured, for example, by the following manufacturing method.

wherein L¹, L², Y, Z, ring A, L³, L⁴, G, R¹, R², R⁴, and R⁵ are defined the same as item 1, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, LG represents a leaving group (e.g., a halogen atom such as chlorine, bromine, or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, an arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy, or the like), T represents a hydroxyl group or a leaving group (e.g., a halogen atom such as chlorine, bromine, or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, an arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy, or the like), PG¹ represents a protecting group of a hydroxyl group (e.g., a tert-butoxycarbonyl group, acetyl group, methoxymethyl group, p-methoxybenzyl group, tert-butyldimethylsilyl group, trimethylsilyl group, or the like), and PG² and PG³ represent protecting groups of boronic acid (e.g., an optionally substituted C₁₋₆ alkyl group, a structure represented by the following formula, or the like).

PG⁴ represents a hydrogen atom, a protecting group of a hydroxyl group (e.g., a tert-butoxycarbonyl group, acetyl group, methoxymethyl group, p-methoxybenzyl group, tert-butyldimethylsilyl group, trimethylsilyl group, or the like), a protecting group of a thiol group (e.g., an acetamidomethyl group or trityl group), or a protecting group of an amino group (e.g., an ethoxycarbonyl group, tert-butoxycarbonyl group, acetyl group, benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, triphenylmethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, benzylsulfonyl group, benzyl group, 4-nitrobenzyl group, 4-methoxybenzyl group, methyl group, ethyl group, or the like).

A commercially available product or a compound manufactured by a known method (e.g., WO 2016/003929, WO 2016/149393, or the like) can be used as a starting raw material compound (1-1).

A commercially available product that is purchased or a compound synthesized in accordance with a method described in a known document (WO 2016/149393, Journal of Heterocyclic Chemistry, 15(8), 1295, 1978, Journal of Heterocyclic Chemistry, 44(2), 279, 2007, Eur. J. Med. Chem., 64, 54, 2013, J. Med. Chem., 2012, 55, 2945, J. Med. Chem., 2005, 48, 1984, Tetrahedron Letters, 57, 2888, 2016, WO 2012/018668, or the like) or a known method (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (1-2).

A commercially available product that is purchased or a compound synthesized in accordance with a method described in a known document (e.g., WO 2008/008895, WO 2011/118818, J. Med. Chem., 28(11), 1721, 1985, Tetrahedron, 67(52), 10208, 2011, Tetrahedron Letters, 26(39), 4739, 1985, J. Antibiot. 59(4), 241, 2006, or the like) or a known method (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (1-5).

As compound (1-2) and compound (1-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 1-1: Compound (1-3) can be manufactured by reacting compound (1-1) with compound (1-2) in an inert solvent in the presence of a base under normal pressure or under pressure. Specific examples of inert solvents include ether solvents such as THF and DME, halogenated hydrocarbon solvents such as dichloromethane or dichloroethane, aprotic solvents such as N,N-dimethylformamide (DMF), —N— methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO), and the like. Examples of base include potassium tert-butoxy, sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, and the like. A base can be used at 0.001 to 100 equivalents with respect to compound (1-1), which is preferably 0.5 to 10 equivalents. Compound (1-2) can be used at 0.001 to 100 equivalents with respect to compound (1-1), which is preferably 1 to 10 equivalents. The reaction temperature is selected from the range of about −10° C. to about 100° C.

Step 1-2: Compound (1-4) can be manufactured by deprotecting the protecting group PG¹ of compound (1-3). This step can be performed in accordance with the method described in, for example, the document (T. W. Greene and P. G. M. Wuts, “Protective Group in Organic Synthesis”, 3^(rd) Ed., John Wiley and Sons, Inc., New York (1999)) or the like.

Step 1-3: Compound (1-6) can be manufactured using Manufacturing Method (1-3-1) or Manufacturing Method (1-3-2) described below.

Step 1-3-1: If Y is an oxygen atom and T is a hydroxyl group, compound (1-6) can be manufactured by reacting compound (1-4) with compound (1-5) under the so-called Mitsunobu reaction in an inert solvent, in the presence of an azo compound analog and organic phosphorous compound or in the presence of a phosphorane compound under normal pressure or under pressure. Specific examples of inert solvents include ether solvents such as THF and DME, hydrocarbon solvents such as toluene and benzene, and the like. Examples of azo compound analog include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and the like. An azo compound analog can be used at 0.001 to 100 molar equivalents with respect to compound (1-4), which is preferably 1 to 10 molar equivalents. Examples of the organic phosphorous compound include triphenylphosphine, tributylphosphine, and the like. An organic phosphorous compound can be used at 0.001 to 100 molar equivalents with respect to compound (1-4), which is preferably 1 to 10 molar equivalents. Examples of phosphorane compounds include (cyanomethylene)tributylphosphorane, (cyanomethylene)trimethylphosphorane, and the like. A phosphorane compound can be used at 0.001 to 100 molar equivalents with respect to compound (1-4), which is preferably −1 to −10 molar equivalents. The reaction temperature is selected from the range of about −10° C. to about 100° C.

Step 1-3-2: If Y is an oxygen atom, a sulfur atom, or —NR^(j)— and T is a leaving group (e.g., a halogen atom such as chlorine, bromine, or iodine, a lower alkylsulfonyloxy group such as a methanesulfonyloxy group, a trihalogenomethanesulfonyloxy group such as a trifluoromethanesulfonyloxy group, an arylsulfonyloxy group such as a benzenesulfonyloxy group or p-toluenesulfonyloxy group, or the like), compound (1-6) can be manufactured by reacting compound (1-4) with compound (1-5) in an inert solvent, in the presence of a base under normal pressure or under pressure. Specific examples of inert solvents include ether solvents such as THF and DME, halogenated hydrocarbon solvents such as dichloromethane and dichloroethane, aprotic solvents such as N,N-dimethylformamide (DMF), —N— methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO), and the like. Examples of bases include potassium tert-butoxy, sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, and the like. A base can be used at 0.001 to 100 molar equivalents with respect to compound (1-1), which is preferably 0.5 to molar equivalents. Compound (1-5) can be used at 0.001 to 100 molar equivalents with respect to compound (1-4), which is preferably 1 to 10 molar equivalents. The reaction temperature is selected from the range of about −10° C. to about 100° C.

Step 1-4: This reaction can manufacture a compound from a corresponding compound (1-6) in accordance with a known method (e.g., WO 2014/151958, WO 2015/191907, WO 2016/003929, or the like). Preferably, a compound can be manufactured using Manufacturing Method (1-4-1) or Manufacturing Method 1-4-2) described below.

Manufacturing Method (1-4-1): Compound (1-7) can be manufactured by using compound (1-6) as a starting material and reacting the compound with boronic acid under acidic conditions in an inert solvent. Examples of boronic acid include phenylboronic acid and 2-methylpropyl boronic acid. The boronic acid can be used in the range of 0.001 to 100 equivalents with respect to compound (1-6), which is preferably 1 to 3 equivalents. Examples of acids include hydrochloric acid, trifluoroacetic acid, and the like. An acid can be used in the range of 0.001 to 100 equivalents with respect to compound (1-6), which is preferably 1 to 10 equivalents. Specific examples of inert solvents include halogenated hydrocarbon solvents such as dichloromethane and dichloroethane, hydrocarbon solvents such as hexane and heptane, ether solvents such as THE and CPME, nitrile solvents such as acetonitrile and propionitrile, and water, which can be used alone or as a mixture solvent. The acids described above can also be directly used as a solvent. A mixture solvent of hexane/acetonitrile is preferably used as a solvent. The reaction temperature is selected from the range of about −10° C. to about 100° C.

Manufacturing Method (1-4-2): Compound (1-7) can be manufactured by using compound (1-6) as the starting material and reacting the compound with triethylsilane in a trifluoroacetic acid solvent. Triethylsilane can be used in the range of 0.001 to 100 equivalents with respect to compound (1-6), which is preferably 1 to 50 equivalents. The reaction temperature is selected from the range of about −10° C. to about 70° C.

Manufacturing Method 1A

A compound of formula (1a) can be purchased or manufactured from a preparable corresponding material in the same manner as the manufacturing method of compound (1-7) described above. The compound is obtained in some cases as a compound of formula (1b), for example, by reacting with a reagent that generates nucleophilic X⁻ (X anion)(e.g., alkali metal salt generating a hydroxide anion HO—, alkali metal salt of C₂₋₄ alkoxide generating a C₁₋₆ alkoxide anion, the alkali metal salt of amide generating amide anion R^(a2)R^(b1)N—, or the like), depending on the property of compound (1a).

wherein X, Z, L¹, L², G, R, R², R³, and R⁴ are defined the same as item 1. For example, a compound of formula (1a′), which is a compound of formula (1a) wherein X is a hydroxyl group, is obtained in some cases as a sodium salt compound of formula (1b′), depending on the property of the compound, by treatment with an aqueous sodium hydroxide solution.

wherein Z, L¹, L², G, R¹, R², R³, and R⁴ are defined the same as item 1. For example, a compound of formula (1a″), which is a compound of formula (1a) wherein X is a hydroxyl group and R⁴ is a carboxyl group, is obtained in some cases as a disodium salt compound of formula (1b″), depending on the property of the compound, by treatment with an aqueous sodium hydroxide solution.

wherein Z, L³, L², G, R³, R², and R³ are defined the same as item 1.

Manufacturing Method 2

Compounds of formula (1a) represented by formula (2-7) described below can be manufactured, for example, by the manufacturing method described below. Compound (2-7) represents compound (1-7) wherein L¹ is —NR^(d)(C═O)— and R^(d) is a hydrogen atom.

wherein L², Y, Z, ring A, L³, L⁴, G, R¹, R², R⁴, and R⁵ are defined the same as item 1, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atomd T, L, PG¹, PG², PG³, and PG⁴ are each defined the same as the definition described in Manufacturing Method 1, and TMS represents a trimethylsiyl group.

A commercially available product that is purchased or a compound manufactured by the method described in Manufacturing Method 1 can be used as the starting material compound (1-1) and compound (1-5). Further, a commercially available product that is purchased or a compound synthesized in accordance with a known method (e.g. the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (2-2) and compound (2-3). As compound (1-5), compound (2-2), and compound (2-3), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 2-1. Compound (2-1) can be manufactured by reacting compound (1-1) with hexamethyldisilazane lithium in an inert solvent under normal pressure or under pressure. Specific examples of inert solvents include ether solvents such as THF and diethyl ether, and the like. Hexamethyldisilazane lithium can be used at 0.001 to 100 equivalents with respect to compound (1-1), which is preferably 1 to 10 equivalents. The reaction temperature is selected from the range of about −78° C. to about 50° C.

Step 2-2: Compound (2-4) can be manufactured by reacting compound (2-1) with compound (2-2) or (2-3) in an inert solvent in the presence or absence of a condensing agent and/or base under normal pressure or under pressure. Specific examples of inert solvents include ether solvents such as THF and DME, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aprotic solvents such as DMF, NMP, and DMSO, and the like. (2-2) or (2-3) can be used at 0.001 to 100 equivalents with respect to compound (2-1), which is preferably 1 to 10 equivalents. Various condensing agents that are used in a conventional method can be used as the condensing agent. Examples thereof include 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (including hydrochloride), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, hydrates thereof, and the like. A condensing agent can be used at 0.001 to 100 equivalents with respect to compound (2-1), which is preferably 1 to 10 equivalents. Examples of bases include diisopropylethylamine, triethylamine, and the like. A base can be used at 0.001 to 100 equivalents with respect to compound (2-1), which is preferably 1 to 10 equivalents. The reaction temperature is selected from the range of about −78° C. to about 100° C.

Step 2-3: Compound (2-5) can be manufactured by using compound (2-4) as a starting material and using conditions in accordance with step 1-2 of Manufacturing Method 1 described above.

Step 2-4: Compound (2-6) can be manufactured by using compound (2-5) as a starting material, and reacting the compound with compound (1-5) by using conditions in accordance with step 1-3 of Manufacturing Method 1 described above.

Step 2-5: Compound (2-7) can be manufactured by using compound (2-6) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 3

A compound of formula (1a) represented by formula (3-7) described below can be manufactured, for example, by the manufacturing method described below.

wherein L¹, L², Z, L³, L⁴, G, R¹, R², R⁴, and R⁵ are defined the same as item 1, m and n are defined the same as item 28, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, T, LG, PG², PG³, and PG⁴ are each defined the same as the definition described in Manufacturing Method 1, PG⁵ represents a protecting group of an amino group (e.g., an ethoxycarbonyl group, tert-butoxycarbonyl group, acetyl group, benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, triphenylmethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, benzylsulfonyl group, benzyl group, 4-nitrobenzyl group, 4-methoxybenzyl group, methyl group, ethyl group, or the like), and J represents a hydroxyl group or a leaving group (e.g., a halogen atom such as chlorine, bromine, or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, an arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy, or the like).

A commercially available product that is purchased or a compound manufactured by the methods described in Manufacturing Method 1 and Manufacturing Method 2 can be used as the starting material compound (3-1) and compound (3-2). Further, a commercially available product that is purchased or a compound synthesized in accordance with a known method (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (3-2) and compound (3-5). As compound (3-2) and compound (3-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 3-1: Compound (3-3) can be manufactured by using compound (3-1) as a starting material, and reacting the compound with compound (3-2) by using conditions in accordance with step 1-3 of Manufacturing Method 1 described above.

Step 3-2: Compound (3-4) can be manufactured by deprotecting the protecting group PG⁵ of compound (3-3). This step can be performed in accordance with the method described in, for example, the document (T. W. Greene and P. G. M. Wuts, “Protective Group in Organic Synthesis”, 3^(rd) Ed., John Wiley and Sons, Inc., New York (1999)) or the like.

Step 3-3: Compound (3-6) can be manufactured by using compound (3-4) as a starting material and using conditions in accordance with step 2-2 of Manufacturing Method 2 described above.

Step 3-4: Compound (3-7) can be manufactured by using compound (3-6) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 4

A compound of formula (1a) represented by formula (4-4) described below can be manufactured, for example, by the manufacturing method described below.

wherein Y, ring A, L³, L⁴, G, R¹, R², R⁴, and R⁵ are defined the same as item 1, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, and T, PG¹, PG², PG³, and PG⁴ are each defined the same as the definition described in Manufacturing Method 1.

A commercially available product that is purchased or a compound manufactured by the method described in Manufacturing Method 1 can be used as the starting material compound (4-1) and compound (1-5). As compound (1-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 4-1: Compound (4-2) can be manufactured by using compound (4-1) as a starting material and using conditions in accordance with step 1-2 of Manufacturing Method 1 described above.

Step 4-2: Compound (4-3) can be manufactured by using compound (4-2) as a starting material, and reacting the compound with compound (1-5) by using conditions in accordance with step 1-3 of Manufacturing Method 1 described above.

Step 4-3: Compound (4-4) can be manufactured by using compound (4-3) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 5

A compound of formula (1a) represented by formula (5-4) described below can be manufactured, for example, by the manufacturing method described below.

wherein L³, L⁴, G, R¹, R², R⁴, and R⁵ are defined the same as item 1, m and n are defined the same as item 28, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, T, PG², PG³, and PG⁴ are each defined the same as the definition described in Manufacturing Method 1, and PG⁵ and J are defined the same as the definitions described in

Manufacturing Method 3.

A commercially available product that is purchased or a compound manufactured by the methods described in Manufacturing Method 1 and Manufacturing Method 3 can be used as the starting material compound (4-1), compound (3-2), and compound (3-5). As compound (3-2) and compound (3-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 5-1: Compound (5-1) can be manufactured by using compound (4-1) as a starting material, and reacting the compound with compound (3-2) by using conditions in accordance with step 3-1 of Manufacturing Method 3 described above.

Step 5-2: Compound (5-2) can be manufactured by using compound (5-1) as a starting material and using conditions in accordance with step 3-2 of Manufacturing Method 3 described above.

Step 5-3: Compound (5-3) can be manufactured by using compound (5-2) as a starting material, and reacting the compound with compound (3-5) by using conditions in accordance with step 3-3 of Manufacturing Method 3 described above.

Step 5-4: Compound (5-4) can be manufactured by using compound (5-3) as a starting material and using conditions in accordance with step 3-4 of Manufacturing Method 3 described above.

Manufacturing Method 6

A compound of formula (1a) represented by formula (6-5) described below can be manufactured, for example, by the manufacturing method described below.

wherein L¹, L², Y, Z, ring A, L³, L⁴, G, R⁴, and R⁵ are defined the same as item 1, wherein one end of Y, R^(1a), and R² each attach to one of three attachable positions denoted as unsubstituted on a benzene ring in the chemical formula, R^(1a) and R^(2a) represent the remaining two without a structure of formula (2) among R¹, R², and R³ defined in item 1 herein, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, and T, LG, PG¹, PG², PG³, and PG⁴ are each defined the same as the definition described in Manufacturing Method 1.

A commercially available product that is purchased or a compound manufactured by the method of Manufacturing Method 1 can be used as the starting material compound (6-1), compound (1-2), and compound (1-5). As compound (3-2) and compound (3-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step (6-1): Compound (6-2) can be manufactured by using compound (6-1) as a starting material, and reacting the compound with compound (1-2) by using conditions in accordance with step 1-1 of Manufacturing Method 1 described above.

Step (6-2). Compound (6-3) can be manufactured by using compound (6-2) as a starting material and using conditions in accordance with step 1-2 of Manufacturing Method 1 described above.

Step (6-3): Compound (6-4) can be manufactured by using compound (6-3) as a starting material, and reacting the compound with compound (1-5) by using conditions in accordance with step 1-3 of Manufacturing Method 1 described above.

Step (6-4): Compound (6-5) can be manufactured by using compound (6-4) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 7

A compound of formula (1a) represented by formula (7-5) described below can be manufactured, for example, by the manufacturing method described below. Said compound represents compound (6-5) wherein L³ is —NR^(d)(C═O)— and R^(d) is a hydrogen atom.

wherein L², Y, Z, ring A, L³, L⁴, G, R⁴, and R⁵ are defined the same as item 1, wherein one end of Y, R^(1a), and R^(2a) each attach to one of three attachable positions denoted as unsubstituted on a benzene ring in the chemical formula, R^(1a) and R^(2a) represent the remaining two without a structure of formula (2) among R¹, R², and R³ defined in item 1 herein, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, T, LG, PG¹, PG², PG³, and PG⁴ are each defined the same as the definition described in Manufacturing Method 1, and TMS represents trimethylsilyl.

A commercially available product that is purchased or a compound manufactured by the method described in Manufacturing Method 1 can be used as the starting material compound (6-1), compound (1-2), and compound (1-5). Further, a commercially available product that is purchased or a compound synthesized in accordance with a known method (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (2-2) and compound (2-3). As compound (2-2), compound (2-3), or compound (1-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 7-1: Compound (7-1) can be manufactured by using compound (6-1) as a starting material and using conditions in accordance with step 2-1 of Manufacturing Method 2 described above.

Step 7-2: Compound (7-2) can be manufactured by using compound (7-3) as a starting material, and reacting the compound with compound (2-2) or compound (2-3) by using conditions in accordance with step 2-2 of Manufacturing Method 2 described above.

Step 7-3: Compound (7-3) can be manufactured by using compound (7-2) as a starting material and using conditions in accordance with step 2-3 of Manufacturing Method 2 described above.

Step 7-4: Compound (7-4) can be manufactured by using compound (7-3) as a starting material, and reacting the compound with compound (1-5) by using conditions in accordance with step 2-4 of Manufacturing Method 2 described above.

Step 7-5: Compound (7-5) can be manufactured by using compound (7-4) as a starting material and using conditions in accordance with step 2-5 of Manufacturing Method 2 described above.

Manufacturing Method 8

A compound of formula (1a) represented by formula (8-4) described below can be manufactured, for example, by the manufacturing method described below.

where L¹, L², Z, L³, L⁴, G, R⁴, and R⁵ are defined the same as item 1, wherein one end of an oxygen atom, R^(1a), and R^(2a) for substitution on a benzene ring each attach to one of three attachable positions denoted as unsubstituted on a benzene ring in the chemical formula, R^(1a) and R^(2a) represent the remaining two without a structure of formula (2) among R¹, R², and R³ defined in item 1 herein, m and n are defined the same as item 28, X^(a) is a hydroxyl group or a C₁₋₅ alkoxy group, H is a hydrogen atom, T, PG², PG³, and PG⁴ are each defined the same as the definitions described in Manufacturing Method 1, and PG⁵ and J are each defined the same as the definitions described in Manufacturing Method 3.

A commercially available product that is purchased or a compound manufactured by the methods described in Manufacturing Method 1 and Manufacturing Method 2 can be used as the starting material compound (6-3). Further, a commercially available product that is purchased or a compound manufactured by the method described in Manufacturing Method 3 can be used as compound (3-2) and compound (3-5). As compound (3-2) and compound (3-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 8-1: Compound (8-1) can be manufactured by using compound (6-3) as a starting material, and reacting the compound with compound (3-2) by using conditions in accordance with step 1-3 of Manufacturing Method 1 described above.

Step 8-2: Compound (8-2) can be manufactured by using compound (8-1) as a starting material and using conditions in accordance with step 3-2 of Manufacturing Method 3 described above.

Step 8-3: Compound (8-3) can be manufactured by using compound (8-3) as a starting material, and reacting the compound with compound (3-5) by using conditions in accordance with step 3-3 of Manufacturing Method 3 described above.

Step 8-4: Compound (8-4) can be manufactured by using compound (8-3) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 9

A compound of formula (1a) represented by formula (9-4) described below can be manufactured, for example, by the manufacturing method described below.

wherein Y, ring A, L³, L⁴, G, R⁴, and R⁵ are defined the same as item 1, wherein one end of Y, R^(1a), and R^(2a) each attach to one of three attachable positions denoted as unsubstituted on a benzene ring in the chemical formula, R^(1a) and R^(2a) represent the remaining two without a structure of formula (2) among R¹, R², and R³ defined in item 1 herein, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, and T, LGa PG¹, PG², PG³, and PG⁴ are each defined the same as the definition described in Manufacturing Method 1.

A commercially available product that is purchased or a compound manufactured by the method described in Manufacturing Method 1 can be used as the starting material compound (9-1) and compound (1-5). As compound (1-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 9-1; Compound (9-2) can be manufactured by using compound (9-1) as a starting material and using conditions in accordance with step 1-2 of Manufacturing Method 1 described above.

Step 9-2: Compound (9-3) can be manufactured by using compound (9-2) as a starting material, and reacting the compound with compound (1-5) by using conditions in accordance with step 1-3 of Manufacturing Method 1 described above.

Step 9-3: Compound (9-4) can be manufactured by using compound (9-3) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 10

A compound of formula (1a) represented by formula (10-4) described below can be manufactured, for example, by the manufacturing method described below.

wherein L³, L⁴, G, R⁴, and R⁵ are defined the same as item 1, T, PG², PG³, and PG⁴ are each defined the same as the definitions described in Manufacturing Method 1, wherein one end of an oxygen atom, R^(1a), and R^(2a) for substitution on a benzene ring each attach to one of three attachable positions denoted as unsubstituted on a benzene ring in the chemical formula, R^(1a) and R^(2a) represent the remaining two without a structure of formula (2) among R¹, R², and R³ defined in item 1 herein, m and n are defined the same as item 28, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, and PG⁵ and J are defined the same as the definitions described in Manufacturing Method 3.

A commercially available product that is purchased or a compound manufactured by the methods described in Manufacturing Method 1 and Manufacturing Method 3 can be used as the starting material compound (9-2), compound (3-2), and compound (3-5). As compound (3-2) and compound (3-5), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 10-1: Compound (10-1) can be manufactured by using compound (9-2) as a starting material, and reacting the compound with compound (3-2) by using conditions in accordance with step 3-1 of Manufacturing Method 3 described above.

Step 10-2: Compound (10-2) can be manufactured by using compound (10-1) as a starting material and using conditions in accordance with step 3-2 of Manufacturing Method 3 described above.

Step 10-3: Compound (10-3) can be manufactured by using compound (10-2) as a starting material, and reacting the compound with compound (3-5) by using conditions in accordance with step 3-3 of Manufacturing Method 3 described above.

Step 10-4: Compound (10-4) can be manufactured by using compound (10-3) as a starting material and using conditions in accordance with step 3-4 of Manufacturing Method 3 described above.

Manufacturing Method 11

A compound of formula (1a) represented by formula (11-3) described below can be manufactured, for example, by the manufacturing method described below. Said compound (11-3) represents compound (3-7) wherein L³ is —S(═O)₂—.

wherein L¹, L², Z, L⁴, G, R¹, R², R⁴, and R⁵ are defined the same as item 1, m and n are defined the same as item 28, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, and PG², PG³, and PG⁴ are each defined the same as the definitions described in Manufacturing Method 1.

A compound manufactured by the method described in Manufacturing Method 3 can be used as the starting material compound (3-4). Further, a commercially available product that is purchased or a compound synthesized in accordance with a known method (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (11-1). As compound (11-1), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 11-1: Compound (11-2) can be manufactured by reacting compound (3-4) with compound (11-1) in an inert solvent in the presence or absence of a base under normal pressure or under pressure. Specific examples of inert solvents include ether solvents such as THF and DME, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aprotic solvents such as DMF, NMP, and DMSO. Compound (11-1) can be used at 0.001 to 100 equivalents with respect to compound (3-4), which is preferably 1 to 10 equivalents. Examples of bases include diisopropylethylamine, triethylamine, and the like. A base can be used at 0.001 to 100 equivalents with respect to compound (3-4), which is preferably 1 to 10 equivalents. The reaction temperature is selected from the range of about −78° C. to about 100° C.

Step 11-2: Compound (11-3) can be manufactured by using compound (11-2) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 12

A compound of formula (1a) represented by formula (12-2) described below can be manufactured, for example, by the manufacturing method described below. Said compound (12-2) represents compound (5-4) wherein L³ is —S(═O)₂—.

wherein L⁴, G, R¹, R², R⁴, and R⁵ are defined the same as item 1, m and n are defined the same as item 28, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, and PG², PG³, and PG⁴ are each defined the same as the definitions described in Manufacturing Method 1.

A compound manufactured by the method described in Manufacturing Method 5 can be used as the starting material compound (5-2). Further, a commercially available product that is purchased or a compound synthesized in accordance with a known method (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (11-1). As compound (11-1), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 12-1: Compound (12-1) can be manufactured by using compound (5-4) as a starting material and using conditions in accordance with step 11-1 of Manufacturing Method 11 described above.

Step 12-2: Compound (12-2) can be manufactured by using compound (12-1) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

Manufacturing Method 13

A compound of formula (1a) represented by formula (13-5) described below can be manufactured, for example, by the manufacturing method described below. Said compound (13-5) represents compound (5-4) wherein R⁵ is optionally substituted 1H-1,2,3-triazole.

wherein L³, L⁴, G, R¹, R², and R⁴ are defined the same as item 1, m and n are defined the same as item 28, X^(a) is a hydroxyl group or a C₁₋₆ alkoxy group, H is a hydrogen atom, U represents an amino group, a nitro group, carboxylic acid, alcohol, or a leaving group (e.g., a halogen atom such as chlorine, bromine, or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, an arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy, or the like), R^(P) is a group that is acceptable as a compound of formula (13-4) in R^(a) defined in item 36 or a group that can be converted into the R^(a), PG², PG³, and PG⁴ are each defined the same as the definitions described in Manufacturing Method 1, and J is defined the same as the definition described in Manufacturing Method 3.

A compound manufactured by the method described in Manufacturing Method 5 can be used as the starting material compound (5-2). Further, a commercially available product that is purchased or a compound synthesized in accordance with a known method (e.g., the method described in R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., John Wiley and Sons, Inc., New York (1999) or the like) from a known compound can be used as compound (13-1). As compound (13-1), a salt thereof can also be used, and the compound with a functional group that is protected can also be used as needed, as long as the reaction is not affected.

Step 13-1: Compound (13-2) can be manufactured using compound (5-4) as a starting material and using conditions in accordance with step 5-3 of Manufacturing Method 5 described above.

Step 13-2: Compound (13-3) can be manufactured by reacting compound (13-2) with an aziding agent in an inert solvent in the presence or absence of a base under normal pressure. Specific examples of inert solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform and aprotic solvents such as DMF, NMP, and DMSO. Specific examples of aziding agents include sodium azide, trimethylsilyl azide, diphenylphosphoryl azide, and the like. An aziding agent can be used at 0.001 to 100 equivalents with respect to compound (13-2), which is preferably 1 to 10 equivalents. Examples of bases include diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, and the like. A base can be used at 0.001 to 100 equivalents with respect to compound (13-2), which is preferably 1 to 10 equivalents. The reaction temperature is selected from the range of about −78° C. to about 100° C.

Step 13-3: Compound (13-5) can be manufactured by reacting compound (13-3) with compound (13-4) in an inert solvent in the presence or absence of a base in the presence or absence of a catalyst under normal pressure or under pressure. Specific examples of inert solvents include ether solvents such as THF and DME, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aprotic solvents such as acetonitrile, DMF, NMP, and DMSO. Compound (13-4) can be used at 0.001 to 100 equivalents with respect to compound (13-3), which is preferably 1 to 10 equivalents. Examples of bases include diisopropylethylamine, triethylamine, and the like. A base can be used at 0.001 to 100 equivalents with respect to compound (13-3), which is preferably 1 to 10 equivalents. Specific examples of catalysts include copper sulfate, copper iodide, and (chloro[(1,2,3,4,5-h)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]bis(triphenylphosphine) ruthenium(II). A catalyst can be used at 0.001 to 100 equivalents with respect to compound (13-3), which is preferably 0.01 to 10 equivalents. The reaction temperature is selected from the range of about −78° C. to about 100° C.

Step 13-4: Compound (12-6) can be manufactured using compound (12-5) as a starting material and using conditions in accordance with step 1-4 of Manufacturing Method 1 described above.

The intermediate and compound of interest in the manufacturing methods described above can be isolated and purified by subjecting them to a purification method that is commonly used in organic synthesis chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, or the like). Each intermediate can also be subjected to the subsequent reaction without any particular purification.

Optically active forms of the compound of the invention can be manufactured by using an optically active starting material or intermediate, or by optically resolving a racemate of the final product or intermediate. Examples of optional resolution methods include, but are not limited to, separation method using an optically active column and a separation method such as fractional crystallization method. A diastereomer of the compound of the invention can be manufactured by, for example, a separation method such as column chromatography or fractional crystallization, but the method is not limited thereto.

A pharmaceutically acceptable salt of a compound represented by formula (1a) or (1b) can be manufactured by, for example, mixing a compound represented by formula (1) with a pharmaceutically acceptable acid or base in a solvent such as water, methanol, ethanol, 2-propanol, ethyl acetate, or acetone, but the manufacturing method is not limited thereto.

As used herein, “or” is used when “at least one or more” of the listed matters in the sentence can be employed. When explicitly described herein as “within the range of two values”, the range also includes the two values themselves.

Reference literatures such as scientific literatures, patents, and patent applications cited herein are incorporated herein by reference to the same extent that the entirety of each document is specifically described.

The present invention has been described while showing preferred embodiments to facilitate understanding. While the present invention is described hereinafter based on the Examples, the above descriptions and the following Examples are provided for the sole purpose of exemplification, not limitation of the present invention. Thus, the scope of the present invention is not limited to the embodiments and Examples that are specifically described herein and is limited only by the scope of claims.

EXAMPLES

While the present invention is described more specifically with Reference Examples, Examples, and Test Examples hereinafter, the preset invention is not limited thereto.

Compounds were identified using proton nuclear magnetic resonance spectrum (¹H-NMR), liquid chromatography-mass spectrometry (LCMS), or the like. Tetramethylsilane was used as an internal standard for nuclear magnetic resonance spectrum.

For column chromatography in the Reference Examples and Examples, Yamazen Corporation's silica gel column, YMC's ODS-A column, and YMC's YMC-Actus Triart C18 were used. For TLC (silica gel plate) in purification using a thin layer chromatography (TLC), Silica gel 60F254 (Merck) was used, and for TLC (NH silica gel plate), TLC plate NH (Fuji Silysia) was used.

Various data described in the Reference Examples and Example was obtained with the following equipment.

NMR spectrum: [¹H-NMR] 400 MHz: JEOL JNM-AL series AL400, JEOL EX270, and 500 MHz: JEOL ECA-500.

600 Hz: Agilent DD2 600 MHz NMR Spectrometer.

LC-MS spectrum: Waters ACQUITY™ UltraPerformance LC, Waters AQUITY UPLC H-Class System, Shimadzu LCMS-2020.

The compound names described in the Reference Examples and Examples were named using ACD/Name (ACD/Labs 12.0, Advanced Chemistry Development Inc.), which are not necessarily in accordance with the IUPAC nomenclature.

The measuring conditions (hereinafter, also referred to as the measurement methods) for a high performance liquid chromatography-mass spectrometry (LCMS) system are described below. The observed mass spectrometry value [MS(m/z)] is indicated by [M+1]⁺, and the time of retention at which the mass spectrometry value was observed is indicated by Rt (min). The measurement conditions A to C used for measurement are denoted in each actual measurement value. For example, “LCMS: [M+H]⁺/Rt=620/1.32^(A)” expresses that measurement was taken under measurement condition A.

Measurement Condition A

Measuring equipment: Waters ACQUITY™ UltraPerformance LC

Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

Solvent: solution A: 0.05% HCOOH/H₂O, solution B: CH₃CN

Gradient Condition:

0.0 to 1.3 minutes; A/B=90/10 to 5/95 (linear gradient)

1.3 to 1.5 minutes; A/B=90/10

Flow rate: 0.80 mL/min

UV: 220 nm, 254 nm

Column temperature: 40° C.

Measurement Condition B

Measuring equipment: Waters AQUITY UPLC H-Class System

Column: Waters AQUITY UPLC HSS T3 1.8 μm 2.1×50 mm column

Solvent: solution A: 0.1% HCO₂H/H₂O, solution B: 0.1% HCO₂H/MeCN

Gradient Condition:

0.0 to 2.4 minutes; A/B=90/10 to 0/100 (linear gradient)

2.4 to 3.2 minutes; A/B=0/100

Flow rate: 0.70 mL/min

UV: 190 to 800 nm

Column temperature: 40° C.

Measurement Condition C

Measuring equipment: Waters ACQUITY™ UltraPerformance LC

Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

Solvent: solution A: 0.05% HCOOH/H₂O, solution B: CH₃CN

Gradient Condition:

0.0 to 1.3 minutes; A/B=99/1 to 5/95 (linear gradient)

1.3 to 1.5 minutes; A/B=99/1

Flow rate: 0.80 mL/min

UV: 220 nm, 254 nm

Column temperature: 40° C.

Measurement Condition D

Measuring equipment: Waters AQUITY UPLC H-Class System

Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column

Solvent: solution A: HCOOH/CH₃CN/H₂O (0.05/50/49.95), solution B: 0.05% HCOOH/CH₃CN

Gradient Condition: 0.0 to 4.0 minutes; A/B=100/0 to 0/100 (linear gradient)

4.0 to 5.0 minutes; A/B=0/100

Flow rate: 0.50 mL/min

UV: 220 nm, 254 nm

Column temperature: 40° C.

Measurement Condition E

Measuring equipment: Waters ACQUITY™ UltraPerformance LC

Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

Solvent: solution A: 0.05% HCOOH/H₂O, solution B: CH₃CN

Gradient Condition:

0.0 to 1.3 minutes; A/B=60/40 to 5/95 (linear gradient)

1.3 to 1.5 minutes; A/B=60/40

Flow rate: 0.80 mL/min

UV: 220 nm, 254 nm

Column temperature: 40° C.

Measurement Condition F

Measuring equipment: Waters ACQUITY™ UltraPerformance LC

Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column

Solvent: solution A: 0.05% HCOOH/H₂O, solution B: CH₃CN

Gradient Condition:

0.0 to 1.3 minutes; A/B=98/2 to 4/96 (linear gradient)

1.3 to 1.5 minutes; A/B=98/2

Flow rate: 0.80 mL/min

UV: 220 nm, 254 nm

Column temperature: 40° C.

Measurement Condition G

Measuring equipment: Shimadzu LCMS-2020

Column: Phenomenex Kinetex 1.7 pim C₁₈ (50 mm×2.10 mm)

Solvent: solution A: 0.05% TFA/H₂O, solution B: CH₃CN

Gradient Condition:

0.0 to 1.9 minutes; A/B=99/1 to 1/99 (linear gradient)

1.91 to 3.00 minutes; A/B=1/99

Flow rate: 0.50 mL/min

UV: 220 nm, 254 nm

Column temperature: 40° C.

Measurement Condition H

Measuring equipment: Shimadzu LCMS-2020

Column: Phenomenex Kinetex 1.7 μm C₁₈ (50 mm×2.10 mm)

Solvent: solution A: 0.05% TFA/H₂O, solution B: CH₃CN

Gradient Condition:

0.0 to 1.9 minutes; A/B=90/10 to 1/99 (linear gradient)

1.91 to 3.00 minutes; A/B=1/99

Flow rate: 0.50 mL/min

UV: 220 nm, 254 nm

Column temperature: 40° C.

Measurement Condition I

Measuring equipment: Waters AQUITY™ UPLC H-Class System

Column: Waters AQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column

Solvent: solution A: 0.05% HCO₂H/H₂O, solution B: 0.05% HCO₂H/MeCN

Gradient Condition:

0.0 to 4.0 minutes; A/B=90/10 to 0/100 (linear gradient)

4.0 to 5.0 minutes; A/B=0/100

Flow rate: 0.50 mL/min

UV: 220, 254 nm

Column temperature: 40° C.

The abbreviations described above and the following abbreviations are used in the Reference Examples, Examples, and Test Examples in some cases to simplify the description.

-   -   s: singlet     -   d: doublet     -   t: triplet     -   q: quadruplet     -   m: multiplet     -   br: broad     -   dd: double doublet     -   J: coupling constant     -   Hz: Hertz     -   δ: chemical shift     -   min: minute     -   THF: tetrahydrofuran     -   DMAP: N,N-dimethyl-4-aminopyridine     -   TFA: trifluoroacetic acid     -   DIPEA: N,N-diisopropylethylamine     -   DMF: dimethylformamide     -   DME: 1,2-dimethoxyethane     -   NMP: N-methylpyrrolidone     -   DMSO: dimethyl sulfoxide     -   Me: methyl     -   Et: ethyl     -   MeCN: acetonitrile     -   CPME: cyclopentyl methyl ether     -   Boc: tert-butoxycarbonyl     -   LBu or ^(t)Bu or t-Bu: tert-butyl     -   t-: tert-     -   Bn: benzyl     -   Cbz: benzyloxycarbonyl     -   Trt: trityl(triphenylmethyl)     -   Ms: methanesulfonyl, mesyl     -   HATU:         1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium         3-oxide hexafluorophosphate     -   N: normal     -   M: mol/L, molarity     -   MEPM: meropenem     -   MIC: minimum inhibitory concentration

Reference Example 1: tert-butyl[1-(3-hydroxyazetidin-1-yl)ethylidene]carbamate

Reference Example 1-1:3-bromo-2,6-dihydroxybenzoic acid

N-bromosuccinimide (6.06 g, 34.1 mmol) was added in small portions to a dichloromethane solution (59 mL) of 2,6-dihydrobenzoic acid (5 g, 32.4 mmol) and —N,N-diisopropylethylamine (2.27 mL, 16.2 mmol) at −78° C. The reaction solution was warmed up to room temperature, and stirred for 20 hours at said temperature. The reaction solution was evaporated under reduced pressure. 1 mol/L hydrochloric acid (40 mL) was added to the resulting residue, and the mixture was stirred for 30 minutes at room temperature. The precipitated crystals were filtered out, washed with water, and dried to obtain the title compound (6.03 g).

¹H-NMR (CDCl₃) δ: 7.58 (1H, d, J=9.2 Hz), 6.53 (1H, d, J=8.5 Hz).

LCMS: [M+H]⁺/Rt=233/0.412 min^(A)

Reference Example 1-2: tert-butyl 3-bromo-2,6-bis[(tert-butoxycarbonyl)oxy]benzoate

Di-tert-butyl dicarbonate (65.2 g, 299 mmol) and DMAP (0.608 g, 4.98 mmol) were added to a THF (120 mL)/tert-butanol (60 mL) solution of the compound of Reference Example 1-1 (11.6 g, 49.8 mmol), and the reaction mixture was stirred for 18 hours at 60° C. The reaction solution was cooled to room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=99/1 to 95/5) to obtain the title compound (19.3 g).

¹H-NMR (CDCl₃) δ: 7.60 (1H, d, J=8.5 Hz), 7.02 (1H, d, J=8.5 Hz), 1.53 (9H, s), 1.51 (9H, s).

Reference Example 1-3: tert-butyl 2,6-bis[(tert-butoxycarbonyl)oxy]-3-ethenylbenzoate

Tri-n-butylvinyltin (2.04 mL, 6.95 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.488 g, 0.695 mmol) were added to a 1,4-dioxane (7 mL) solution of the compound of Reference Example 1-2 (1.7 g, 3.47 mmol) under a nitrogen atmosphere, and the reaction mixture was stirred for 10 hours at 110° C. After cooling the reaction solution to room temperature, the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (1.26 g).

¹H-NMR (CDCl₃) δ: 7.57 (1H, d, J=9.2 Hz), 7.11 (1H, d, J=8.5 Hz), 6.73 (1H, dd, J=17.7, 11.3 Hz), 5.74 (1H, d, J=17.7 Hz), 5.37 (1H, d, J=10.4 Hz), 1.57 (9H, s), 1.54 (9H, s), 1.52 (9H, s).

Reference Example 1-4: tert-butyl 2,6-bis[(tert-butoxycarbonyl)oxy]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]benzoate

1,4-bis(diphenylphosphino)butane (0.547 g, 1.28 mmol), bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.431 g, 0.641 mmol), and pinacolatodiboron (1.40 mL, 9.62 mmol) were added to a dichloromethane (32 mL) solution of the compound of Reference Example 1-3 (2.8 g, 6.41 mmol) under a nitrogen atmosphere, and the reaction mixture was stirred for 17 hours at room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (3.59 g).

¹H-NMR (CDCl₃) δ: 7.30 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=8.5 Hz), 2.66-2.58 (2H, m), 1.53 (9H, s), 1.51 (9H, s), 1.51 (9H, s), 1.20 (12H, s), 1.10-1.02 (2H, m).

Reference Example 1-5: tert-butyl 2,6-bis[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

(1S,2S,3R,5S)-(+)-pinanediol (0.736 g, 4.32 mmol) was added to a THF (5 mL) solution of the compound of Reference Example 1-4 (0.976 g, 1.73 mmol), and the reaction mixture was stirred for 62 hours at room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=99/1 to 85/15) to obtain the title compound (0.90 g).

¹H-NMR (CDCl₃) δ: 7.31 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=7.9 Hz), 4.23 (1H, dd, J=8.5, 1.8 Hz), 2.69-2.60 (2H, m), 2.35-2.24 (1H, m), 2.20-2.11 (1H, m), 2.04-1.97 (1H, m), 1.91-1.76 (2H, m), 1.54 (9H, s), 1.51 (18H, s), 1.34 (3H, s), 1.26 (3H, s), 1.14-1.07 (2H, m), 1.02 (1H, d, J=11.0 Hz), 0.81 (3H, s).

LCMS: [M−H]⁺/Rt=615/3.160 min^(B)

Reference Example 1-6: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-hydroxy-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Pyrrolidine (0.121 mL, 1.46 mmol) was added to a THF (5 mL) solution of the compound of Reference Example 1-5 (0.899 g, 1.46 mmol), and the reaction mixture was stirred for 3 hours at room temperature. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10 to 70/30) to obtain the title compound (0.68 g).

¹H-NMR (CDCl₃) δ: 11.26 (1H, s), 7.33 (1H, d, J=8.5 Hz), 6.82 (1H, d, J=8.5 Hz), 4.24 (1H, dd, J 8.8, 2.1 Hz), 2.63-2.54 (2H, m), 2.37-2.25 (1H, m), 2.23-2.11 (1H, m), 2.04-2.00 (1H, m), 1.93-1.78 (2H, m), 1.61 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.01 (3H, m), 0.83 (3H, S).

LCMS: [M−H]⁺/Rt=515/3.175 min^(B)

Reference Example 1-7: benzyl 3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxyl]azetidine-1-carboxylate

Under a nitrogen atmosphere, cesium carbonate (4.01 g) was added to a DMF (20.5 mL) solution of the compound of Reference Example 1-6 (2.117 g) and benzyl 3-iodoazetidine-1-carboxylic acid (1.95 g), and the reaction mixture was heated to 50° C. After 9 hours, the reaction mixture was cooled to room temperature. The reaction mixture was poured into water, extracted with a mixture solvent of ethyl acetate/hexane (1:1), and concentrated, and the residue was purified by using a silica gel column to obtain the title compound (2.46 g).

¹H-NMR (CDCl₃) δ: 7.36-7.26 (5H, m), 7.18 (1H, d, J=8.5 Hz), 6.36 (1H, d, J=8.5 Hz), 5.08 (2H, s), 4.91-4.84 (1H, m), 4.37-4.27 (2H, m), 4.24-4.18 (1H, m), 4.09-4.03 (2H, m), 2.58 (2H, t, J=8.2 Hz), 2.32-2.25 (1H, m), 2.18-2.08 (1H, m), 2.04-1.95 (1H, m), 1.89-1.84 (1H, m), 1.82-1.74 (1H, m), 1.53 (9H, s), 1.51 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.08 (2H, t, J=8.2 Hz), 1.00 (1H, d, J=11.0 Hz), 0.81 (3H, s).

Reference Example 1-8: tert-butyl 6-[(azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate monohydrochloride

1 N hydrochloric acid (0.567 mL) and 50% water containing 10% palladium on carbon (0.149 g) were added to a methanol (16 mL) solution of the compound of Reference Example 1-7 (0.4 g), and the reaction mixture was stirred for 1 hour under hydrogen atmosphere. After celite filtration, the filtrate was concentrated to obtain the title compound (0.357 g).

¹H-NMR (CD₃OD) δ: 7.31 (1H, d, J=8.5 Hz), 6.66 (1H, d, J=8.5 Hz), 5.14 (1H, m), 4.55-4.42 (2H, m), 4.29-4.22 (1H, m), 4.13-4.05 (2H, m), 2.55 (2H, t, J=8.2 Hz), 2.35-2.30 (1H, m), 2.17-2.13 (1H, m), 1.99-1.92 (1H, m), 1.87-1.80 (1H, m), 1.79-1.72 (1H, m), 1.56 (9H, s), 1.50 (9H, s), 1.33 (3H, s), 1.27 (3H, s), 1.04 (2H, t, J=8.2 Hz), 0.98-0.96 (1H, m), 0.83 (3H, s).

Reference Example 1: tert-butyl 6-[(1-acetylazetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Acetic anhydride (0.023 mL) and triethylamine (0.057 mL) were added to a THF (0.8 mL) solution of the compound of Reference Example 1-8 (0.1 g) in an ice bath, and the reaction mixture was stirred overnight at room temperature. After concentration, the mixture was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (0.105 g).

¹H-NMR (CDCl₃) δ: 7.19 (1H, d, J=8.5 Hz), 6.39 (1H, d, J=8.5 Hz), 4.93-4.88 (1H, m), 4.46-4.30 (2H, m), 4.24-4.18 (1H, m), 4.16-4.00 (2H, m), 2.59 (2H, t, J=8.7 Hz), 2.35-2.23 (1H, m), 2.20-2.09 (1H, m), 2.01-1.96 (1H, m), 1.91-1.82 (4H, m), 1.82-1.73 (1H, m), 1.54 (9H, s), 1.49 (9H, d, J a 15.8 Hz), 1.32 (3H, t, J=7.0 Hz), 1.25 (3H, s), 1.10 (2H, t, J=8.7 Hz), 1.03-0.97 (1H, m), 0.81 (3H, s).

Reference Example 2: tert-butyl 6-[(1-methylsulfonylazetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 1 to obtain the title compound.

¹H-NMR (CDCl₃) δ: 7.20 (1H, d, J=8.5 Hz), 6.41 (1H, d, J=8.5 Hz), 4.93-4.87 (1H, m), 4.29-4.20 (3H, m), 4.00-3.97 (2H, m), 2.89 (3H, s), 2.61-2.57 (2H, m), 2.33-2.26 (1H, m), 2.15 (1H, ddd, J=13.7, 6.1, 3.4 Hz), 2.00 (1H, t, J=5.5 Hz), 1.87 (1H, td, J=6.3, 3.9 Hz), 1.78 (1H, dt, J=14.6, 2.7 Hz), 1.55 (9H, s), 1.51 (9H, s) 1.34 (3H, s), 1.26 (3H, s), 1.11-1.06 (2H, m), 1.00 (2H, d, J=11.0 Hz), 0.81 (3H, s).

Reference Example 3: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3-{2-[(3aS,4S,6S,7aR)-3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

HATU was added to a DMF (0.905 mL) solution of the compound of Reference Example 1-8 (0.11 g), 4-imidazoleacetic acid hydrochloride (0.059 g), and triethylamine (0.076 mL) in an ice bath. The reaction mixture was slowly warmed up to room temperature, and stirred for 18 hours. The reaction mixture was poured into water, extracted with a mixture solvent of ethyl acetate/hexane (2:1), and concentrated, and the residue was purified by using a silica gel column to obtain the title compound (0.096 g).

¹H-NMR (CDCl₃) δ: 8.19 (1H, s), 7.21 (1H, d, J=8.5 Hz), 7.00 (1H, s), 6.39 (1H, d, J=8.5 Hz), 4.90 (1H, m), 4.61-4.59 (1H, m), 4.31-4.27 (1H, m), 4.23-21 (1H, m), 4.7-4.05 (1H, m), 3.81-78 (1H, m), 3.54 (2H, s), 2.58 (2H, m), 2.30-2.26 (2H, m), 2.17-2.13 (1H, m), 2.02-1.98 (1H, m), 1.88-1.87 (1H, m), 1.80-1.77 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.33 (3H, s), 1.25 (3H, s), 1.10-1.06 (2H, m), 1.22-1.10 (1H, s), 0.81 (3H, s).

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 3 to obtain each of Reference Example compounds 4 to 34 shown in Table 2.

TABLE 2 Reference Example Structural formula NMR and/or LCMS  4

¹H-NMR (CDCl₃) δ: 7.31- 7.23 (18H, m), 7.19 (1H, d, J = 8.5 Hz), 6.96 (1H, s), 6.56 (1H, s), 6.35 (1H, d, J = 8.5 Hz), 4.93 (1H, ddd, J = 11.3, 5.8, 3.7 Hz), 4.46 (1H, dd, J = 11.0, 6.7 Hz), 4.32 (1H, dd, J = 9.2, 6.7 Hz), 4.22 (1H, dd, J = 8.5, 1.8 Hz), 4.16- 4.04 (3H, m), 4.01 (4H, t, J = 10.7 Hz), 2.59 (2H, t, J = 8.2 Hz), 2.33-2.26 (1H, m), 2.15 (1H, tt, J = 10.7, 3.5 Hz), 1.99 (3H, t, J = 5.8 Hz), 1.89-1.85 (1H, m), 1.78 (1H, dt, J = 14.6, 2.7 Hz), 1.65 (2H, t, J = 6.1 Hz), 1.55-1.46 (19H, m), 1.37-1.29 (4H, m), 1.27 (4H, d, J = 9.8 Hz), 1.07 (2H, dd, J = 15.3, 7.3 Hz), 1.01 (1H, t, J = 7.6 Hz), 0.81 (3H, s).  5

¹H-NMR (CDCl₃) δ: 8.54 (1H, d, = 4.3 Hz), 8.10 (1H, d, J = 7.9 Hz), 7.79- 7.77 (1H, m), 7.35-7.32 (1H, m), 7.21 (1H, d, J = 8.5 Hz), 6.44 (1H, d, = 8.5 Hz), 5.09-5.06 (1H, m), 4.98-4.97 (1H, m), 4.70-4.67 (1H, m), 4.58- 4.55 (1H, m), 4.30-4.19 (2H, m), 2.60 (2H, t, J = 8.2 Hz), 2.31-2.28 (1H, m), 2.18-2.13 (1H, m), 2.02- 1.99 (1H, m), 1.87 (1H, br s), 1.81-1.77 (1H, m), 1.53 (9H, s), 1.51 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.10 (2H, t, = 7.9 Hz), 1.01 (1H, d, J = 11.0 Hz), 0.81 (3H, s).  6

¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.6 Hz), 6.42 (1H, d, J = 8.6 Hz), 5.30 (2H, s), 5.00-4.90 (1H, m), 4.60-4.52 (1H, m), 4.46- 4.36 (1H, m), 4.28-4.08 (4H, m), 3.07 (2H, s), 2.66- 2.58 (2H, m), 2.39-2.24 (1H, m), 2.22-2.12 (1H, m), 2.07-1.99 (1H, m), 1.93-1.76 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14- 1.01 (3H, m), 0.84 (3H, s).  7

¹H-NMR (CDCl₃) δ: 8.19 (1H, s), 7.24 (1H, d, J = 8.6 Hz), 6.46 (1H, d, J = 8.6 Hz), 5.18-5 00 (2H, m) 4.76-4.58 (2H, m), 4.14- 4.09 (2H, m), 2.62 (2H, t, J = 8.2 Hz), 2.38-2.25 (1H, m), 2.23-2.09 (1H, m), 2.07-1.99 (1H, m), 1.93- 1.75 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.34 (3H, s), 1.28 (3H, s), 1.12 (2H, t, J = 8.2 Hz), 1.07-1.00 (1H, m), 0.84 (3H, s).  8

¹H-NMR (CDCl₃) δ: 8.20- 8.17 (1H, m), 7.55-7.51 (1H, m), 7.38-7.12 (4H, m), 6.39 (1H, d, J = 8.6 Hz). 5.13-4.96 (1H, m), 4.77- 4.61 (2H, m), 4.28-4.23 (2H, m), 4.14-4.05 (1H, m), 2.72-2.55 (2H, m), 2.32- 2.25 (1H, m), 2.23-2.10 (1H, m), 2.07-1.98 (1H, m), 1.95-1.74 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.35 (3H, s), 1.28 (3H, 2), 1.13- 1.00 (3H, m), 0.83 (3H, s).  9

¹H-NMR (CDCl₃) δ: 7.43- 7.28 (4H, m), 7.23-7.14 (1H, m), 6.40-6.27 (1H, m), 5.97-5.78 (1H, m), 5.22- 5.10 (1H, m), 4.99-471 (1H, m), 4.65-4.37 (1H, m), 4.35-4.18 (2H, m), 4.18- 4.04 (1H, m), 4.04-3.77 (1H, m), 2.66-2.54 (2H, m), 2.38-2.24 (1H, m), 2.205-1.98 (1H, m), 1.94- 1.85 (1H, m), 1.84-1.74 (1H, m), 1.57 (9H, m), 1.54-1.48 (9H, m), 1.42- 1.36 (9H, m), 1.35 (3H, s), 1.28 (3H, s), 1.14-0.94 (1H, m), 0.83 (3H, s). 10

¹H-NMR (CDCl₃) δ: 7.67- 7.59 (2H, m), 7.50-7.36 (3H, m), 7.23-7.19 (1H, d, J = 8.6 Hz), 6.41 (1H, d, J = 8.6 Hz), 5.05-4.95 (1H, m), 4.64-4.50 2H, m), 4.39-4.30 (3H, m), 2.73- 2.55 (2H, m), 2.39-2.25 (1H, m), 2.25-2.09 (1H, m), 2.08-1.96 (1H, m), 1.95-1.75 (2H, m), 1.60- 1.75 (18H, m), 1.37-1.23 (6H, m), 1.22-0.96 (3H, m), 0.86-0.80 (3H, m). 11

LCMS: [M + H]⁺/Rt = 678/2.75 min^(B) 12

LCMS: [M + H]⁺/Rt = 692/2.62 min^(B) 13

LCMS: [M + H]⁺/Rt = 692/2.53 min^(B) 14

LCMS: [M + H]⁺/Rt = 828/3.06 min^(B) 15

LCMS: [M + H]⁺/Rt = 692/2.79 min^(B) 16

¹H-NMR (CDCl₃) δ: 7.32- 7.26 (2H, m), 7.23-7.17 (1H, m), 7.16-7.00 (2H, m), 6.43-6.36 (1H, m), 4.95-4.86 (1H, m), 4.46- 4.30 (2H, m), 4.29-4.20 (1H, m), 4.18-4.06 (2H, m), 3.55-3.40 (2H, m), 2.68-2.55 (2H, m), 2.39- 2.24 (1H, m), 2.22-2.10 (1H, m), 2.08-1.98 (1H, m), 1.95-1.73 (2H, m), 1.62-1.49 (27H, m), 1.36 (3H, s), 1.28 (3H, m), 1.14-1.01 (3H, m), 0.83 (3H, s). 17

LCMS: [M + H]⁺/Rt = 922/3.08 min^(B) 18

LCMS: [M + H]⁺/Rt = 682/2.63 min^(B) 19

LCMS: [M + H]⁺/Rt = 852/3.06 min^(B) 20

¹H-NMR (CDCl₃) δ: 7.37- 7.17 (6H, m), 6.42-6.34 (1H, m), 4.94-4.84 (1H, m), 4.44-4.32 (2H, m), 4.29- 4.19 (1H, m), 4.18-4.02 (2H, m), 3.50 (2H, s), 2.68- 2.54 (2H, m), 2.38-2.26 (1H, m), 2.24-2.10 (1H, m), 2.06-1.98 (1H, m), 1.95- 1.73 (2H, m), 1.54 (9H, s), 1.54 (9H, s) 1.36 (3H, s), 1.28 (3H, m), 1.13-1.00 (3H, m), 0.83 (3H, s). 21

LCMS: [M + H]⁺/Rt = 705/2.98 min^(B) 22

LCMS: [M + H]⁺/Rt = 681/2.22 min^(B) 23

LCMS: [M + H]⁺/Rt = 682/2.66 min^(B) 24

LCMS: [M + H]⁺/Rt = 683/2.62 min^(B) 25

LCMS: [M + H]⁺/Rt = 820/3.06 min^(B) 26

LCMS: [M + H]⁺/Rt = 936/3.12 min^(B) 27

LCMS: [M + H]⁺/Rt = 810/2.20 min^(B) 28

LCMS: [M + H]⁺/Rt = 772/3.01 min^(B) 29

LCMS: [M + H]⁺/Rt = 810/2.20 min^(B) 30

LCMS: [M + H]⁺/Rt = 874/2.87 min^(B) 31

LCMS: [M + H]⁺/Rt = 770/3.01 min^(B) 32

LCMS: [M + H]⁺/Rt = 770/3.01 min^(B) 33

LCMS: [M + H]⁺/Rt = 824/2.20 min^(B) 34

¹H-NMR (CD₃OD) δ: 7.34 (2H, d, J = 8.5 Hz), 7.30- 7.29 (3H, m), 7.22-7.20 (2H, m), 7.06 (1H, d, J = 8.5 Hz), 6.89 (2H, d, J = 8.5 H), 6.84 (2H, d, J = 8.5 Hz), 6.63 (1H, d, J = 8.5 Hz), 5.07 (2H, s), 5.06 (2H, s), 5.05-5.02 (1H, m), 4.52-4.49 (2H, m), 4.27 (1H, d, J = 7.3 Hz), 4.10-4.08 (2H, m), 3.77 (3H, s), 3.74 (3H, s), 2.57 (2H, t, J = 8.2 Hz), 2.34-2.31 (1H, m), 2.16- 2.15 (1H, m), 1.97 (1H, t, J = 5.5 Hz), 1.84 (1H, br s), 1.78-1.75 (1H, m), 1.53 (9H, s), 1.51 (9H, s), 1.33 (3H, s), 1.26 (3H, s), 1.07 (2H, t, J = 7.9 Hz), 0.96-0.94 (1H, m), 0.84 (3H, s).

Reference Example 35: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Triphosgene (14.92 mg) was added to a toluene solution of the compound of Reference Example 1-8 (76.4 mg) and DIPEA (0.066 mL) at ° C., The reaction mixture was returned to room temperature and stirred for 1.5 hours. The reaction mixture was concentrated. DMF (2.5 mL), DIPEA (0.5 mL), and hydroxylamine hydrochloride (51 mg) were added to the residue, and the reaction mixture was stirred for 3 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography to obtain the title compound (56.5 mg) as a colorless solid.

¹H-NMR (CDCl₃) δ: 7.12 (1H, d, J=8.5 Hz), 7.04 (1H, S), 7.00 (1H, br s), 6.33 (1H, d, J=8.5 Hz), 4.87-4.83 (1H, m), 4.34 (2H, dd, J=9.8, 6.7 Hz), 4.17 (1H, dd, J=8.5, 1.8 Hz), 4.06-4.01 (2H, m), 2.53 (2H, t, J=8.5 Hz), 2.28-2.21 (1H, m), 2.13-2.07 (1H, m), 1.95 (1H, t, J=5.5 Hz), 1.83-1.81 (1H, m), 1.75-1.72 (1H, m), 1.49 (9H, s), 1.46 (9H, s), 1.29 (3H, s), 1.21 (3H, s), 1.03 (2H, t, J=8.5 Hz), 0.96 (1H, d, J=10.4 Hz), 0.76 (3H, s).

Reference Example (R)-36: tert-butyl 6-({1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate Reference Example (S)-36: tert-butyl 6-({1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 36-1:4-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide

Dimethylsulfamoyl chloride (91 mL, 859 mmol) was added dropwise to a chloroform solution (750 ml) of 1H-imidazole-4-carbaldehyde (75 g, 78 mmol) and triethylamine (163 mL, 1.17 mol) over 50 minutes at room temperature. The reaction solution was stirred for 3 days and then water (900 mL) was added, and the mixture was extracted with chloroform (500 mL, 3 times). The organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the title compound (161 g) as a white solid with a brownish tinge.

¹H-NMR (CDCl₃) δ: 9.88 (1H, br s), 7.91 (1H, t, J=7.3 Hz), 7.84 (1H, dd, J=8.5, 1.2 Hz), 2.87 (6H, dd, J=9.8, 5.5 Hz).

Reference Example 36-2: amino(1H-imidazol-4-yl)acetic acid dihydrochloride

Sodium cyanide (46.7 g, 953 mmol) was added to an ethanol solution (227 mL) of the compound of Reference Example 36-1 (161 g, 794 mmol) and 28t aqueous ammonia (371 mL) while being cooled with ice (internal temperature of 14° C.). The reaction solution was stirred for 4 hours at room temperature and then extracted with chloroform (500 mL, 4 times). The organic phase was dried over sodium sulfate, filtered, and concentrated. 6 N aqueous hydrochloric acid (850 mL) was added to the resulting solid residue, and the reaction mixture was refluxed for 4 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The resulting solid residue was stirred and washed with a THF-ethanol mixture solvent (1:1, 750 mL) and filtered to obtain the title compound (160 g) as a yellow solid with a brownish tinge.

¹H-NMR (D₂O) δ: 8.69 (1H, s), 7.54 (1H, s), 5.14 (1H, s).

Reference Example 36-3: [(tert-butoxycarbonyl)amino](1H-imidazol-4-yl) acetic acid hydrochloride

An aqueous 3 N sodium hydroxide solution (374 mL) was added dropwise to a methanol solution (194 mL) of the compound of Reference Example 36-2 (80 g, 374 mmol) over 45 minutes while cooling with ice. After stirring the reaction solution for 15 minutes while cooling with ice, di-tert-butyl dicarbonate was added over 15 minutes. The reaction solution was stirred for 45 minutes while cooling with ice and then warmed up to room temperature. To the reaction solution, N,N-dimethyl-4-aminopyridine (2.28 g, 18.7 mmol) and 2,2,2-trifluoroethanol (53.4 mL, 747 mmol) were added at room temperature, and the reaction solution was refluxed for 2 hours. After the reaction solution was allowed to cool down, 6 N aqueous hydrochloric acid (25 mL) was added while cooling with ice to adjust the pH of the solution to 6.0. After stirring for 1 hour while cooling with ice, the precipitated solid was filtered out, washed with acetone-water mixture solvent (1:1, 1 L), and dried and solidified under reduced pressure to obtain the title compound (40.0 g) as a white solid.

¹H-NMR (D₂O) 5: 8.50 (1H, d, J=1.2 Hz), 7.27 (1H, s), 5.04 (1H, s), 1.30 (9H, s).

Reference Example 36: tert-butyl 6-({1-[2-({tert-butoxycarbonyl}amino)-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Triethylamine (1.54 ml, 11.1 mmol), 1-hydroxybenzotriazole (0.747 g, 5.53 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.689 g, 3.59 mmol) were added to a DMF solution (9.21 mL) of the compound of Reference Example 36-3 (1.0 g, 4.15 mmol) while cooling with ice. After stirring for 1 hour while cooling with ice, N,N-dimethyl-4-aminopyridine (0.068 g, 0.553 mmol) and the compound of Reference Example 1-8 (1.68 g, 2.76 mmol) were added to the reaction solution. After stirring for 24 hours at room temperature, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic phase was dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to obtain the title compound (1.09 g) as a while amorphous compound.

LCMS: [M+H]⁺/Rt=795.44/0.845 min^(E)

The compound of Reference Example 36 (amount charged per injection: 19.6 mg) was dissolved in 0.300 mL of ethyl acetate. Isomers were obtained by optical resolution by chiral chromatography under the following conditions.

Column: CHIRALPAK IG 20 mmφ×250 mm (Daicel Corporation)

Mobile phase: diethylamine/ethyl acetate (diethylamine: 0.1%)

Flow rate: 10 mL/min

Temperature: 40° C.

Column retention times for both optical isomers were as follows.

-   -   (R)-36: 6.056 min     -   (S)-36: 4.225 min

Reference Example 37. tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](1-methyl-1H-imidazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 37-1: [(tert-butoxycarbonyl)amino](1-methyl-1H-imidazol-4-yl) acetic acid

Sodium hydrogen carbonate (1.09 g, 13.0 mmol) and di-tert-butyl dicarbonate (1.30 mL, 5.62 mmol) were added to a methanol/water (1:1, 8.6 mL) solution of amino(1-methyl-1H-imidazol-4-yl) acetic acid (670 mg, 4.32 mmol), and the reaction mixture was stirred at room temperature. After 2 hours, the reaction solution was concentrated, and the residue was dissolved in ethanol (17 mL). Potassium hydrogen sulfate (2.35 g) was added at 0° C. to quench the reaction. Solids were filtered out, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0 to 40/60) to obtain the title compound (400 mg) as a yellow solid.

LCMS: [M+H]⁺/Rt=255.94/0.419 min^(C)

Reference Example 37: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](1-methyl-1H-imidazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (325 mg, 0.535 mmol) and the compound of Reference Example 37-1 (205 mg, 0.803 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (130 mg).

LCMS: [M+H]⁺/Rt=809.58/1.246 min^(C)

Reference Example 38: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](2-methyl-1H-imidazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 38-1: [(tert-butoxycarbonyl)amino][1-(tert-butoxycarbonyl)-2-methyl-1H-imidazol-4-yl]acetic acid

Di-tert-butyl dicarbonate (1.64 g, 7.52 mmol) was added to a methanol solution (10 mL) of methyl 2-amino-2-(2-methyl-1H-imidazol-4-yl)acetate dihydrochloride (0.828 g, 3.42 mmol), N,N-dimethyl-4-aminopyridine (0.084 g, 0.684 mmol), and triethylamine (1.91 mL, 13.7 mmol) at room temperature, and the reaction mixture was stirred. After the completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate and concentrated to obtain the title compound (0.59 g).

¹H-NMR (CD₃OD) δ: 7.31 (1H, s), 4.91 (1H, s), 2.53 (3H, s), 1.60 (9H, s), 1.42 (9H, s).

Reference Example 38-2: potassium [(tert-butoxycarbonyl)amino](2-methyl-1H-imidazol-4-yl)acetate

Potassium carbonate (0.331 g, 2.40 mmol) was added to a methanol solution (3.2 mL) of the compound of Reference Example 38-1 (0.59 g, 1.60 mmol). After stirring for 30 minutes at room temperature, the aqueous layer was washed with ethyl acetate and concentrated to obtain the title compound (0.47 g).

¹H-NMR (CD₃OD) δ: 6.77 (1H, s), 4.98 (1H, s), 2.29 (3H, s), 1.43 (9H, s).

Reference Example 38: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](2-methyl-1H-imidazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (0.328 g, 0.539 mmol) and the compound of Reference Example 38-2 (0.234 g, 0.799 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (68.3 mg).

LCMS: [M+H]⁺/Rt=809.50/1.162 min^(C)

Reference Example 39: tert-butyl 6-[(1-{2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)propanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 39-1: methyl amino(1H-imidazol-4-yl)acetate dihydrochloride

Thionyl chloride (75 mL, 1.21 mol) was added dropwise to a methanol solution (265 mL) of the compound of Reference Example 36-2 (44 g, 206 mmol) while cooling with ice. The reaction solution was warmed up to room temperature and then stirred for 9 hours at 50° C. The reaction solution was concentrated under reduced pressure to obtain the title compound (46.9 g) as a light yellow oily substance.

LCMS: [M+H]⁺/Rt=155.93/0.142 min^(C)

Reference Example 39-2: tert-butyl 4-{1-[(tert-butoxycarbonyl)amino]-2-methoxy-2-oxoethyl}-1H-imidazole-carboxylate

N,N-dimethyl-4-aminopyridine (0.113 g, 0.928 mmol), triethylamine (0.863 mL, 6.19 mmol), and di-tert-butyl dicarbonate (1.08 mL, 4.64 mmol) were added to a chloroform solution (20 mL) of the compound of Reference Example 39-1 (0.70 g, 3.09 mmol) at room temperature, and the reaction mixture was stirred for 24 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (1.10 g) as a colorless oily substance.

¹H-NMR (CD₃OD) δ: 8.14 (1H, d, J=1.2 Hz), 7.51 (1H, s), 5.27 (1H, s), 3.73 (3H, s), 1.63 (9H, s), 1.45 (9H, s).

Reference Example 39-3: tert-butyl 4-{2-[(tert-butoxycarbonyl)amino]-1-methoxy-1-oxopropan-2-yl}-1H-imidazole-1-carboxylate

A lithium bis(trimethylsilyl)amide/THE solution (1.3 mol/L, 19.6 mL, 25.4 mmol) was added to a THF solution (43 mL) of the compound of Reference Example 39-2 (4.3 g, 12.1 mmol) at −78° C., and the reaction mixture was stirred for 30 minutes. Methyl iodide (0.832 mL, 13.3 mmol) was added to the reaction solution at −78° C. The reaction solution was warmed up to room temperature, and stirred for 4 hours. Saturated saline was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (2.15 g) as a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 8.00 (1H, d, J=1.2 Hz), 7.35 (1H, d, J=1.2 Hz), 6.08 (1H, s), 3.73 (3H, s), 1.91 (3H, s), 1.61 (9H, s), 1.43 (9H, s).

Reference Example 39-4: 2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl)propanoic acid

Lithium hydroxide monohydrate (0.513 g, 12.2 mmol) was added to a methanol solution (11.6 mL) of the compound of Reference Example 39-3 (2.15 g, 5.82 mmol) at room temperature, and the reaction mixture was stirred for 3 hours. 6 N aqueous hydrochloric acid (2.1 mL) was added, and the reaction mixture was stirred for 4 hours. Saturated saline was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain the title compound (1.49 g) as a crude product.

Reference Example 39: tert-butyl 6-[(1-{2-[(tert-butoxycarbonyl)amino]-2-(1H-imidazol-4-yl) propanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (0.30 g, 0.493 mmol) and the compound of Reference Example 39-4 (0.176 g, 0.691 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (153 mg).

LCMS: [M+H]⁺/Rt=809.17/1.139 min^(C)

Reference Example 40: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(1H-imidazole-4-carbonyl)azetidin-3-yl]oxy}-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl)benzoate

Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMP (3 mL), and triethylamine (0.118 mL, 0.850 mmol) and 1H-imidazole-5-carboxylic acid chloride (40.7 mg, 0.312 mmol) were added. The reaction mixture was stirred for 20 minutes at room temperature, then water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain the title compound (149 mg) as a light yellow solid.

¹H-NMR (CDCL₃) δ: 7.77-7.55 (2H, m), 7.26-722 (1H, m), 7.46 (1H, d, J=8.1 Hz), 5.12-4.90 (2H, m), 4.66-4.40 (2H, m), 4.30-4.15 (2H, m), 2.65-2.59 (2H, m), 2.36-2.26 (1H, m), 2.23-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.70 (2H, m), 1.59 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.15-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=666.7/2.49 min^(B)

Reference Example 41: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(4H-1,2,4-triazole-3-sulfonyl)azetidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in methylene chloride (3 mL), and triethylamine (0.118 mL, 0.850 mmol) was added. A methylene chloride solution (3 mL) of 1H-1,2,4-triazole-3-sulfonyl chloride (47.5 mg, 0.283 mmol) was added while cooling with ice, and the reaction mixture was stirred for 5 minutes. Water was added to the reaction solution, which was extracted with methylene chloride. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (205 mg) as a colorless solid.

¹H-NMR (CDCl₃) δ: 8.37 (1H, s), 7.20 (1H, d, J=8.1 Hz), 6.26 (1H, d, J=8.1 Hz), 4.43-4.37 (2H, m), 4.24 (1H, dd, J=8.1 Hz, 2.7 Hz), 4.16-4.08 (3H, m), 2.62-2.56 (2H, m), 2.36-2.27 (1H, m), 2.21-2.12 (1H, m), 2.05-2.00 (1H, m), 1.92-1.76 (2H, m), 1.55 (9H, s), 1.52 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.12-0.99 (3H, m), 0.83 (3H, s).

LCMS: [M+H]⁺/Rt=703.6/2.75 min^(B)

Reference Example 42: tert-butyl 6-({1-[N²-(tert-butoxycarbonyl)-L-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in THF (3 mL), and tert-butoxycarbonyl-L-asparagine (85.6 mg, 0.368 mmol), N,N′-dicyclohexylcarbodiimide (58.5 mg, 0.340 mmol), 1-hydroxybenzotriazole monohydrate (52.1 mg, 0.340 mmol), and N-methylmorpholine (34.3 μL, 0.312 mmol) were added, and the reaction mixture was stirred for 2 hours at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (198 mg) as a colorless solid.

¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J=8.1 Hz), 6.41-6.37 (1H, m), 6.03 (1H, br), 5.72-5.61 (1H, m), 5.48-5.39 (1H, m), 4.99-4.89 (1H, m), 4.75-4.51 (2H, m), 4.44-4.31 (2H, m), 4.27-4.23 (1H, m), 4.10-4.03 (1H, m), 2.73-2.56 (4H, m), 2.36-2.27 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.92-1.77 (2H, m), 1.57 (9H, s), 1.53 (9H, s), 1.43 (9H, s), 1.36 (3H, s), 1.26 (3H, 9), 1.14-1.01 (3H, m), 0.83 (3H, s).

LCMS: [M+H]⁺/Rt=786.8/2.79 min^(B)

Reference Example 43: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 43-1: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[1-(chloroacetyl)azetidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Under a nitrogen atmosphere, a dichloromethane (5.3 mL) solution of the compound of Reference Example 1-8 (160 mg, 0.263 mmol) was cooled with ice to 0° C. Chloroacetyl chloride (30 μL, 0.377 mmol) and triethylamine (0.11 mL, 0.789 mmol) were added, and the reaction mixture was stirred for 1 hour at room temperature. Subsequently, the reaction solution was cooled with ice, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous ammonium chloride solution and saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the title compound (140 mg).

¹H-NMR (CDCl₃) δ: 7.21 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=8.6 Hz), 4.99-4.93 (1H, m), 4.64-4.58 (1H, m), 4.44-4.39 (1H, m), 4.32-4.27 (1H, m), 4.24-4.20 (1H, m), 4.15-4.09 (1H, m), 3.89 (2H, s), 2.60 (2H, t, J=8.3 Hz), 2.34-2.26 (1H, m), 2.18-2.12 (1H, m), 2.02-1.98 (1H, m), 1.91-1.85 (1H, m), 1.82-1.75 (1H, m), 1.56-1.51 (18H, m), 1.34 (3H, s), 1.26 (3H, s), 1.11-1.07 (2H, m), 1.00 (1H, d, J=10.9 Hz), 0.81 (3H, s).

Reference Example 43-2: tert-butyl 6-{[1-(azidoacetyl)azetidin-3-yl]oxy}-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Sodium azide (69.0 mg, 1.06 mmol) was added to a DMSO (4.3 mL) solution of the compound of Reference Example 43-1 (140 mg, 0.216 mmol), and the reaction mixture was stirred for 1.5 hours at room temperature. Subsequently, water was added to the reaction solution, which was diluted with ethyl acetate, and the organic phase was separated. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the title compound (129 mg).

¹H-NMR (CDCl₃) δ: 7.25-7.21 (1H, M), 6.41 (1H, d, J=8.6 Hz), 5.01-4.93 (1H, m), 4.55-4.48 (1H, m), 4.48-4.40 (1H, m), 4.27-4.19 (2H, m), 4.17-4.11 (1H, m), 3.84-3.72 (2H, m), 2.61 (2H, t, J=8.3 Hz), 2.36-2.28 (1H, m), 2.20-2.13 (1H, m), 2.04-1.99 (1H, m), 1.92-1.86 (1H, m), 1.83-1.77 (1H, m), 1.59-1.51 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.09 (2H, m), 1.04-0.99 (1H, m), 0.83 (3H, s).

Reference Example 43: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

2-propyn-1-ol (47 μL, 0.788 mmol), copper iodide (24.4 mg, 0.128 mmol), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (24.3 mg, 46.0 μmol) were added to an acetonitrile (9.2 mL) solution of the compound of Reference Example 43-2 (300 mg, 0.458 mmol), and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, a saturated aqueous potassium sodium tartrate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=50/1 to 30/1) to obtain the title compound (271 mg).

¹H-NMR (CDCl₃) δ: 7.75 (1H, s), 7.23 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=8.6 Hz), 5.13-5.05 (11H, m), 5.02-4.93 (2H, m), 4.81 (2H, s), 4.56-4.50 (1H, m), 4.47-4.38 (1H, m), 4.27-4.22 (1H, m), 4.21-4.09 (2H, m), 2.66-2.59 (2H, m), 2.38-2.28 (2H, m), 2.22-2.14 (1H, m), 2.05-1.99 (1H, m), 1.93-1.87 (1H, m), 1.84-1.77 (1H, m), 1.57 (9H, s), 1.54 (9H, s), 1.36 (3H, d, J=1.1 Hz), 1.28 (3H, s), 1.14-1.08 (2H, m), 1.06-1.01 (1H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=711.42/3.75 min^(D)

Reference Example 44: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

The compound of Reference Example 43-2 (74.9 mg, 0.114 mmol) and (chloro[(1,2,3,4,5-h)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]bis(triphenylphosphine) ruthenium(II) (900 μg, 1.14 μmol) were added to a toluene (0.91 mL) solution of 2-propyn-1-ol (11.0 μL, 0.182 mmol), and the reaction mixture was stirred for 19 hours at 80° C. Subsequently, the reaction solution was cooled to room temperature, and stirred again for 4 hours at 80° C. after adding 2-propyn-1-ol (11.0 μL, 0.182 mmol) and chloro[(1,2,3,4,5-h)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]bis(triphenylphosphine)ruthenium(II) (900 μg, 1.14 μmol). Subsequently, the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1 to chloroform/methanol=10/1) to obtain the title compound (45.3 mg).

¹H-NMR (CDCl₃) δ: 7.62 (1H, s), 7.22 (1H, d, J=8.6 Hz), 6.41 (1H, d, J=8.6 Hz), 5.14-5.08 (1H, m), 5.02-4.93 (2H, m), 4.71-4.62 (3H, m), 4.42-4.36 (1H, m), 4.29-4.19 (3H, m), 2.60 (2H, t, J=8.3 Hz), 2.36-2.26 (1H, m), 2.20-2.13 (1H, m), 2.03-1.99 (1H, m), 1.92-1.76 (3H, m), 1.56 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.27 (3H, s), 1.13-1.07 (2H, m), 1.04-0.99 (1H, m), 0.82 (3H, s).

LCMS: [M+H]⁺/Rt=711.60/3.75 min^(D)

Reference Example 45: tert-butyl 6-({1-[(5-{([(tert-butoxycarbonyl)(methyl)amino]methyl}-1H-1, 2, 3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 43-2 as the starting material by the same method described in Reference Example 44 to obtain the title compound.

¹H-NMR (CDCl₃) δ: 7.59 (1H, s), 7.21 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 5.23-5.07 (2H, m), 5.01-4.90 (1H, m), 4.62-4.36 (4H, m), 4.29-4.19 (2H, m), 4.13-4.05 (1H, m), 2.82 (3H, s), 2.59 (2H, t, J=8.3 Hz), 2.34-2.26 (1H, m), 2.20-2.11 (1H, m), 2.04-1.96 (1H, m), 1.91-1.85 (1H, m), 1.82-1.75 (1H, m), 1.57-1.51 (18H, m), 1.43 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.12-1.07 (2H, m), 1.01 (1H, d, J=10.9 Hz), 0.81 (3H, s).

LCMS: [M+H]⁺/Rt=824.80/4.16 min^(D)

Reference Example 46: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[4-(2-tert-butoxy-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 46-1: benzyl[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]acetate

Water (12 mL) was added to a tert-butyl alcohol (12 mL) solution of benzyl 2-azidoacetate (2.50 g, 13.0 mmol). Sodium L-ascorbate (527 mg, 2.66 mmol), 3-butyn-1-ol (1.5 mL, 19.8 mmol), and copper sulfate pentahydrate (347 mg, 1.39 mmol) were added, and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, water was added to the reaction solution, which was extracted with chloroform. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=100/1 to 30/1) to obtain the title compound (3.13 g).

¹H-NMR (CDCl₃) δ: 7.52-7.50 (1H, m), 7.38-7.31 (5H, m), 5.21 (2H, s), 5.16 (2H, s), 3.95 (2H, q, J=6.1 Hz), 2.96 (2H, t, J=5.4 Hz).

LCMS: [M+H]⁺/Rt=262.09/1.88 min^(D)

Reference Example 46-2: {1-[2-(benzyloxy)-2-oxoethyl]-1H-1,2,3-triazol-4-yl}acetic acid

An aqueous 0.67M sodium dihydrogen phosphate solution (28 mL) was added to an acetonitrile (28 mL) solution of the compound of Reference Example 46-1 (1.02 g, 3.90 mmol). 2,2,6,6-tetramethylpiperidine-1-oxyl (56.3 mg, 0.360 mmol), aqueous 5% hypochlorous acid solution (2.1 mL), and aqueous 80% chlorous acid solution (0.88 mL, 7.81 mmol) were added, and the reaction mixture was stirred for 23 hours at room temperature. Subsequently, an aqueous sodium thiosulfate solution was added to the reaction solution, which was then extracted with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, which was again extracted with chloroform. The organic phase was washed with saturated saline and 1M hydrochloric acid, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure to obtain the title compound (676 mg).

¹H-NMR (CDCl₃) δ: 7.73 (1H, s), 7.37-7.31 (5H, m), 5.21 (2H, s), 5.18 (2H, s), 3.90 (2H, s).

Reference Example 46-3: benzyl tert-butyl 2,2′-(1H-1,2,3-triazol-1,4-diyl)diacetate

Under a nitrogen atmosphere, a THE (15 mL) solution of the compound of Reference Example 46-2 (676 mg, 2.46 mmol) was cooled with ice. tert-butyl alcohol (10 mL) and N,N′-diisopropyl-O-t-butylisourea (1.8 mL, 0.789 mmol) were added, and the reaction mixture was stirred for 17 hours at room temperature. The reaction solution was evaporated under reduced pressure, and then the resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (425 mg).

¹H-NMR (CDCl₃) δ: 7.72 (1H, s), 7.39-7.31 (5H, m), 5.21 (2H, s), 5.16 (2H, s), 3.75 (2H, s), 1.45 (9H, s).

Reference Example 46-4: (4-(2-tert-butoxy-2-oxoethyl)-1H-1,2,3-triazol-1-yl)acetic acid

10% palladium on carbon (88.7 mg) was added to an ethyl acetate (12 mL) solution of the compound of Reference Example 46-3 (397 mg, 1.20 mmol). Under a hydrogen atmosphere, the reaction mixture was stirred for 50 minutes at room temperature. Subsequently, the reaction solution was filtered through celite and then the filtrate was evaporated under reduced pressure to obtain the title compound (288 mg).

¹H-NMR (CD₃OD) δ: 7.91 (1H, s), 5.19 (2H, s), 3.70 (2H, s), 1.45 (9H, s).

Reference Example 46: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-{[4-(2-tert-butoxy-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy)-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

The compound of Reference Example 1-8 (503 mg, 0.828 mmol), triethylamine (0.350 mL, 2.51 mmol), 1-hydroxybenzotriazole (231 mg, 1.71 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (237 mg, 1.71 mmol) were added to a DMF solution (8.3 mL) of the compound of Reference Example 46-4 (277 mg, 1.15 mmol) while cooling with ice. After stirring for 1.5 hours at room temperature, water was added to the reaction solution, which was then extracted with a hexane/ethyl acetate (1:1) mixture solution. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid, and saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/2 to 1/3) to obtain the title compound (394 mg).

¹H-NMR (CDCl₃) δ: 7.78 (1H, s), 7.22 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 5.10-4.90 (3H, m), 4.50-4.38 (2H, m), 4.27-4.10 (3H, m), 3.76 (2H, s), 2.61 (2H, t, J=8.3 Hz), 2.36-2.28 (1H, m), 2.21-2.14 (1H, m), 2.06-2.00 (1H, m), 1.92-1.87 (1H, m), 1.84-1.76 (1H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.08 (2H, m), 1.03 (1H, d, J=10.9 Hz), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=795.55/4.19 min^(D)

Reference Example 47: [4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetic acid

Reference Example 47-1: tert-butyl 6-{[1-({1-[2-(benzyloxy)-2-oxyethyl]-1H-1,2,3-triazol-4-yl}acetyl)azetidin-3-yl]oxy}-2-[(tert-butoxycarbonyl)oxy]-2-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 36-4 to obtain the title compound.

¹H-NMR (CDCl₃) δ: 7.77 (1H, s), 7.39-7.31 (5H, m), 7.22 (1H, d, J=8.6 Hz), 6.40 (1H, d, J=8.6 Hz), 5.22 (2H, s), 5.18 (2H, d, J=1.7 Hz), 4.96-4.89 (1H, m), 4.66-4.61 (1H, m)), 4.40-4.34 (1H, m), 4.29-4.22 (2H, m), 4.11-4.05 (1H, m), 3.72-3.58 (2H, m), 2.64-2.58 (2H, m), 2.36-2.28 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.92-1.87 (1H, m), 1.83-1.77 (1H, m), 1.59-1.52 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.09 (2H, m), 1.03 (1H, d, J=10.9 Hz), 0.83 (3H, 8).

LCMS: [M+H]⁺/Rt=829.46/4.22 min^(D)

Reference Example 47: [4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S, 7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-1,2,3-triazol-1-yl]acetic acid

A suspension of 10% palladium on carbon (67.9 mg) in ethyl acetate was added to a methanol (4.1 mL) solution of the compound of Reference Example 47-1 (340 mg, 0.410 mmol). Subsequently, under a hydrogen atmosphere, the reaction mixture was stirred for 2 hours at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (271 mg).

¹H-NMR (CDCl₃) δ: 7.78 (1H, s), 7.21 (1H, d, J=8.6 Hz), 6.39 (1H, d, J=8.0 Hz), 5.17-4.99 (2H, m), 4.98-4.88 (1H, m), 4.61-4.55 (1H, m), 4.41-4.31 (1H, m), 4.27-4.22 (1H, m), 4.14-4.01 (2H, m), 3.70-3.62 (2H, m), 2.60 (2H, t, J=8.3 Hz), 2.37-2.13 (2H, m), 2.04-1.99 (1H, m), 1.92-1.86 (1H, m), 1.83-1.77 (1H, m), 1.55 (9H, s), 1.53 (9H, 8), 1.36 (3H, s), 1.28 (3H, s), 1.10 (2H, t, J=8.3 Hz), 1.03 (1H, d, J=10.9 Hz), 0.83 (3H, s).

LCMS: [M+H]⁺/Rt=739.28/3.84 min^(D)

Reference Example 48: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino][1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 48-1: methyl[(tert-butoxycarbonyl)amino](1H-imidazol-4-yl)acetate

Sodium hydrogen carbonate (1.03 g, 12.2 mmol) and di-tert-butyl dicarbonate (2.06 mL, 8.95 mmol) were added to a THF-water (3:1) mixture solution (18 mL) of the compound of Reference Example 39-1 (928 mg, 4.07 mmol). The reaction mixture was stirred for 20 hours at room temperature and then stirred for 2 days at 70° C. After allowing the reaction solution to cool, water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain the title compound (368 mg) as a light yellow solid.

¹H-NMR (CDCl₃) δ: 7.60 (1H, s), 7.06 (1H, s), 5.74 (1H, br), 5.40 (1H, d, J=8.1 Hz), 3.76 (3H, s), 1.45 (9H, s).

LCMS: [M+H]⁺/Rt=256.2/0.93 min^(B)

Reference Example 48-2: methyl[(tert-butoxycarbonyl)amino][1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-4-yl]acetate

Sodium hydride (23.4 mg, 60% dispersion in liquid paraffin, 0.586 mmol) was added to a DMF solution (2.1 mL) of the compound of Reference Example 48-1 (136 mg, 0.533 mmol) under a nitrogen atmosphere at 0° C., and the reaction mixture was stirred for 30 minutes at room temperature. tert-butyl bromoacetate (86.0 μL, 0.586 mmol) was added, and the reaction mixture was stirred for 3 hours. Methanol (0.1 mL) and then saturated saline (20 mL) were added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (155 mg) as a light yellow solid.

¹H-NMR (CDCl₃) δ: 7.43 (1H, s), 6.98 (1H, s), 5.76 (1H, d, J=8.1 Hz), 5.34 (1H, d, J=8.1 Hz), 4.55 (2H, s), 3.75 (3H, s), 1.47 (9H, s), 1.40 (9H, s).

LCMS: [M+H]⁺/Rt=370.7/1.59 min^(B)

Reference Example 48-3: [(tert-butoxycarbonyl)amino][1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-4-yl]acetic acid

Triethylamine (0.291 mL, 2.10 mmol) was added to an aqueous solution (4.2 mL) of the compound of Reference Example 48-2 (155 mg, 0.420 mmol), and the reaction mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain the title compound (84.9 mg) as a colorless solid.

¹H-NMR (CDCl₃) δ: 7.82 (1H, s), 7.01 (1H, s), 5.97 (1H, s), 5.30 (1H, s), 4.62 (2H, 9), 1.48 (9H, s), 1.44 (9H, s).

LCMS: [M+H]⁺/Rt=356.2/1.35 min^(B)

Reference Example 48: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino][1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (3 mL). Reference Example 48-3 (131 mg, 0.368 mmol), HATU (129 mg, 0.340 mmol), and triethylamine (0.118 mL, 0.850 mmol) were added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain the title compound (208 mg) as a colorless amorphous compound.

¹H-NMR (CDCl₃) δ: 7.42 (1H, d, J=2.7 Hz), 7.20 (1H, dd, J=8.1 Hz, 5.4 Hz), 6.97 (1H, d, J=5.4 Hz), 6.36 (1H, d, J=5.4 Hz), 5.86-5.71 (1H, m), 5.26 (1H, d, J=8.1 Hz), 4.98-4.82 (1H, m), 4.76-4.05 (7H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.20-2.13 (1H, m), 2.04-2.00 (1H, m), 1.92-1.77 (2H, m), 1.61 (9H, s), 1.53 (9H, s), 1.48-1.42 (18H, m), 1.36 (3H, s), 1.26 (3H, s), 1.13-1.01 (3H, m), 0.83 (3H, s).

LCMS: [M+H]⁺/Rt=910.2/2.97 min^(B)

Reference Example 49: tert-butyl 6-[(1-{[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl][(tert-butoxycarbonyl)amino]acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 49-1: methyl[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl][(tert-butoxycarbonyl)amino]acetate

Sodium hydroxide (70.5 mg, 60% dispersion in liquid paraffin, 1.76 mmol) was added to a DMF solution (6.4 mL) of the compound of Reference Example 48-1 (409 mg, 1.60 mmol) under a nitrogen atmosphere at 0° C., and the reaction mixture was stirred for 30 minutes at room temperature. 2-bromoacetamide (243 mg, 1.76 mmol) was added, and the reaction mixture was stirred for 1.5 hours. Methanol (0.1 mL) was added to the reaction solution, and the mixture was purified by silica gel column chromatography (eluent: methylene chloride/methanol) to obtain a mixture (564 mg) of the title compound and a regioisomer thereof. The resulting mixture was further purified by silica gel column chromatography (amine silica gel, eluent: ethyl acetate/methanol). The resulting mixture (396 mg) of the title compound and a regioisomer thereof was triturated in methylene chloride, filtered, and dried and solidified under reduced pressure to obtain the title compound (198 mg) as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 7.51 (1H, s), 7.47-7.19 (3H, m), 7.10 (1H, s), 5.19 (1H, d, J=8.1 Hz), 4.59 (2H, s), 3.62 (3H, s), 1.39 (9H, s).

LCMS: [M+H]⁺/Rt=313.2/0.66 min^(B)

Reference Example 49-2: [1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl][(tert-butoxycarbonyl)amino]acetic acid·1/2(triethylamine) salt

Triethylamine (0.204 mL, 1.47 mmol) was added to an aqueous solution (3.0 mL) of the compound of Reference Example 49-1 (92.0 mg, 0.295 mmol), and the reaction mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (123 mg) as a colorless amorphous compound.

¹H-NMR (CD₃OD) δ: 7.69 (1H, s), 7.08 (1H, s), 5.03 (1H, s), 4.72 (2H, s), 3.62 (3H, s), 3.18 (3H, q, J=8.1 Hz), 1.42 (9H, s), 1.29 (4.5H, t, J=8.1 Hz).

LCMS: [M+H]⁺/Rt=299.4/0.50 min^(B)

Reference Example 49: tert-butyl 6-[(1-{[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl][(tert-butoxycarbonyl)amino]acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) and the compound of Reference Example 49-2 (109 mg, 0.312 mmol) as the starting materials by the same method described in Reference Example 42 to obtain the title compound (130 mg) as a colorless solid.

¹H-NMR (CDCl₃) b: 7.46 (1H, s), 7.21 (1H, dd, J=8.1 Hz, 5.4 Hz), 6.97-6.95 (1H, m), 6.41-6.37 (1H, m), 5.88-5.59 (3H, m), 5.25-5.22 (1H, m), 5.00-4.87 (1H, m), 4.83-4.57 (3H, m), 4.48-4.33 (1H, m), 4.27-4.23 (1H, m), 4.16-4.05 (2H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.19-2.13 (1H, m), 2.04-2.00 (1H, m), 1.92-1.77 (2H, m), 1.62-1.53 (18H, m), 1.43 (9H, s), 1.36 (3H, 9), 1.26 (3H, s), 1.13-1.00 (3H, m), 0.83 (3H, s).

LCMS: [M+H]⁺/Rt=853.0/2.49 min^(B)

Reference Example 50: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](1H-1,2,3-triazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 50-1: ethyl(1-benzyl-1H-1,2,3-triazol-4-yl)(hydroxy)acetate

After adding benzylazide (0.10 mL), copper iodide (44.6 mg, 0.234 mmol), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (41.4 mg, 78.0 μmol) to an acetonitrile (7.8 mL) solution of ethyl 2-hydroxy-3-butynoate (91 μL, 0.780 mmol) and stirring the reaction mixture for 5 hours at room temperature, a saturated aqueous potassium sodium tartrate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic phase was washed with saturated saline, and then dried over anhydrous sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/2) to obtain the title compound (187 mg).

¹H-NMR (CDCl₁) 5: 7.45 (1H, s), 7.38-7.33 (3H, m), 7.27-7.23 (2H, m), 5.50 (2H, s), 5.34 (1H, d, J=5.7 Hz), 4.33-4.18 (2H, m), 3.44 (1H, d, J=6.3 Hz), 1.24 (3H, t, J=7.2 Hz).

Reference Example 50-2: ethyl(1-benzyl-1H-1,2,3-triazol-4-yl)[(methanesulfonyl)oxy]acetate

Under a nitrogen atmosphere, triethylamine (0.12 mL, 0.856 mmol) and methanesulfonyl chloride (36 μL, 0.476 mmol) were added to a dichloromethane (1.9 mL) solution of the compound of Reference Example 50-1 (102 mg, 0.389 mmol), and the reaction mixture was stirred for 4 hours at 0° C. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure to obtain the title compound (110 mg).

¹H-NMR (CDCl₃) δ: 7.59 (1H, s), 7.39-7.36 (3H, m), 7.28-7.25 (2H, m), 6.16 (1H, s), 5.57-5.47 (2H, m), 4.33-4.22 (2H, m), 3.14 (3H, s), 1.27-1.24 (3H, m).

Reference Example 50-3: ethyl azide(1-benzyl-1H-1,2,3-triazol-4-yl)acetate

Under a nitrogen atmosphere, a DMF (4.0 mL) solution of the compound of Reference Example 50-2 (156 mg, 0.406 mmol) was cooled with ice. Sodium azide (39.6 mg, 0.609 mmol) was added, and the reaction mixture was stirred for 3.5 hours while cooling with ice. Subsequently, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=2/1 to 1/1) to obtain the title compound (88.7 mg).

¹H-NMR (CDCl₃) δ: 7.56 (1H, s), 7.40-7.37 (3H, m), 7.29-7.26 (2H, m), 5.55 (2H, s), 5.14 (1H, s), 4.34-4.19 (2H, m), 1.30-1.25 (3H, m).

Reference Example 50-4: ethyl[(tert-butoxycarbonyl)amino](1H-1,2,3-triazol-4-yl)acetate

The compound of Reference Example 50-3 (101 mg, 0.349 mmol) and di-tert-butyl dicarbonate (114 mg, 0.524 mmol) were added to an ethanol (12 mL) solution of 10% palladium on carbon (10.4 mg), and then, under a hydrogen atmosphere, the reaction mixture was stirred for 2 hours at room temperature. Subsequently, 1M hydrochloric acid (0.35 mL) was added to the reaction solution, and the reaction mixture was further stirred for 44 hours at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (98.9 mg).

¹H-NMR (CDCl₃) δ: 7.74 (1H, s), 5.81-5.49 (2H, m), 4.34-4.09 (2H, m), 1.44 (9H, s), 1.27-1.21 (3H, m).

Reference Example 50-5: [(tert-butoxycarbonyl)amino](1H-1, 2, 3-triazol-4-yl) acetic acid

Lithium hydroxide monohydrate (14.1 mg, 0.336 mmol) was added to a THF/water (3:1) mixture solution (1.7 mL) of the compound of Reference Example 50-4 (45.4 mg, 0.168 mmol), and the reaction mixture was stirred for 3 hours at room temperature. Subsequently, 1M hydrochloric acid was added until the pH was 4, and the mixture was extracted with ethyl acetate, and then the aqueous layer was extracted again with chloroform. The organic phase was washed with saturated saline, and then dried over sodium sulfate and filtered, then the filtrate was evaporated under reduced pressure. The resulting residue was washed and purified by decantation with diethyl ether to obtain the title compound (12.7 mg).

¹H-NMR (CD₃OD) δ: 7.93-7.65 (1H, m), 5.51-5.32 (1H, m), 1.45 (9H, s).

Reference Example 50: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](1H-1,2,3-triazol-4-yl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and the compound of Reference Example 50-5 as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound.

¹H-NMR (CDCl₃) δ: 7.71-7.62 (1H, m), 7.24-7.17 (1H, m), 6.39-6.32 (1H, m), 5.96-5.78 (1H, m), 5.52-5.37 (1H, m), 5.04-4.84 (1H, m), 4.62-3.93 (5H, m), 2.67-2.58 (2H, m), 2.51-2.27 (1H, m), 2.25-2.12 (1H, m), 2.04-1.99 (1H, m), 1.95-1.86 (1H, m), 1.83-1.74 (1H, m), 1.66-1.26 (33H, m), 1.14-1.08 (2H, m), 1.04-0.99 (1H, m), 0.83 (3H, s).

LCMS: [M+H]⁺/Rt=796.42/2.30 min^(D)

Reference Example 51: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 51-1: tert-butyl (4-nitro-1H-1,2,3-triazol-1-yl)acetate

1-(dimethylamino)-2-nitroethylene (1.57 g, 13.5 mmol) was added to a 1,4-dioxane (8.2 mL) solution of tert-butyl 2-azidoacetate (1.29 g, 8.21 mmol), and the reaction mixture was stirred for 12 hours under microwave irradiation at 120° C. Subsequently, the reaction solution was evaporated under reduced pressure to obtain the title compound (226 mg).

¹H-NMR (CDCl₃) δ: 8.45 (1H, s), 5.13 (2H, s), 1.50 (9H, s).

LCMS: [M+H]⁺/Rt=229.13/2.48 min^(D)

Reference Example 51-2: (4-nitro-1H-1,2,3-triazol-1-yl)acetic acid

A 4 N hydrogen chloride-1,4-dioxane solution (14 mL) was added to the compound of Reference Example 51-1 (329 mg, 1.44 mmol), and the reaction mixture was stirred for 23 hours at room temperature. Subsequently, the reaction solution was evaporated under reduced pressure to obtain the title compound.

¹H-NMR (CD₃OD) δ: 8.94 (1H, s), 5.35-5.30 (2H, m).

Reference Example 51: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and the compound of Reference Example 51-2 as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound.

¹H-NMR (CDCl₃) δ: 8.57 (1H, s), 6.43 (1H, d, J=8.6 Hz), 5.16-4.98 (3H, m), 4.65-4.57 (1H, m), 4.48-4.41 (1H, m), 4.36-4.29 (1H, m), 4.26-4.21 (1H, m), 4.20-4.13 (1H, m), 2.66-2.56 (2H, m), 2.33-2.28 (1H, m), 2.18-2.13 (1H, m), 2.05-1.97 (1H, m), 1.91-1.85 (1H, m), 1.82-1.75 (2H, m), 1.55 (9H, s), 1.52 (9H, s), 1.34 (3H, s), 1.26 (3H, 9), 1.12-1.07 (2H, m), 1.03-0.98 (1H, m), 0.82 (3H, s).

Reference Example 52: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-D-serylazetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 52-1: tert-butyl 6-[(1-(N-[(benzyloxy)carbonyl]-D-seryl)azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (114.4 mug, 0.188 mmol) and N-carbobenzoxy-D-serine (91.8 mg, 0.384 mmol) as the starting materials by the same method described in Reference Example 3 to obtain the title compound (71.4 mg).

¹H-NMR (CD₃OD) b: 7.39-7.26 (6H, in), 6.67 (1H, d, J=8.5 Hz), 5.12-5.05 (3H, m), 4.39-4.33 (1H, in), 4.29 (2H, d, J=8.5 Hz), 4.00-3.94 (1H, m), 3.74-3.67 (2H, m), 3.34 (2H, s), 2.58 (2H, t, J=7.9 Hz), 2.39-2.32 (1H, m), 2.21-2.16 (1H, m), 1.99 (1H, t, J=5.5 Hz), 1.89-1.87 (1H, m), 1.79 (1H, d, J=15.3 Hz), 1.55 (9H, d, J=7.9 Hz), 1.52 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.08 (2H, t, J=8.2 Hz), 0.99 (1H, d, J=10.4 Hz), 0.86 (3H, s).

LCMS: [M+H]⁺/Rt=793.48/1.381 min^(A)

Reference Example 52: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[(1-D-serylazetidin-3-yl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Palladium on carbon (20 mg, Pd content: 10t, wetted with ca. 55% water) was added to a methanol solution (3.0 mL) of the compound of Reference Example 52-1 (200 mg, 0.252 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated to obtain the title compound (198 mg).

¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J=8.1 Hz), 6.44-6.40 (1H, m), 5.01-4.94 (1H, m), 4.71-4.06 (5H, m), 3.74-3.49 (3H, m), 2.64-2.58 (2H, m), 2.45-2.00 (6H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=659.7/2.31 min$

Reference Example 53: tert-butyl 6-({1-[N²-(tert-butoxycarbonyl)-N-methyl-D-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl)benzoate

Reference Example 53-1: tert-butyl 6-[(1-{(2R)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and benzyl (R)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoate as the starting materials by the same method described in Reference Example 3 to obtain the title compound (1.84 g).

¹H-NMR (CDCl₃) δ: 7.40-7.31 (5H, m), 7.21 (1H, d, J=8.6 Hz), 6.40-6.30 (1H, m), 5.37-5.24 (1H, m), 5.16-5.07 (2H, m), 4.97-4.54 (3H, m), 4.42-4.27 (2H, m), 4.27-4.22 (1H, m), 4.08-4.00 (1H, m), 2.84-2.73 (2H, m), 2.65-2.57 (2H, m), 2.37-2.27 (1H, m), 2.24-2.13 (1H, m), 2.04-2.00 (1H, m), 1.93-1.87 (1H, m), 1.84-1.77 (1H, m), 1.56 (9H, s), 1.53 (9H, s), 1.44-1.40 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.15-1.08 (2H, m), 1.06-1.01 (1H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=877.72/4.54 min^(D)

Reference Example 53-2: (3R)-3-[(tert-butoxycarbonyl)amino]-4-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-4-oxobutanoic acid

A suspension of 10% palladium on carbon (150 mg) in ethyl acetate was added to an ethyl acetate (17 mL) solution of the compound of Example 53-1 (1.50 g, 1.71 mmol). Subsequently, under a hydrogen atmosphere, the reaction mixture was stirred for 3 hours at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (1.34 g).

¹H-NMR (CD₃OD) δ: 7.32 (1H, d, J=8.0 Hz), 6.69 (1H, d, J=8.6 Hz), 5.15-5.08 (1H, m), 4.63-4.59 (1H, m), 4.55-4.27 (4H, m), 3.99-3.92 (1H, m), 2.82-2.69 (1H, m), 2.61-2.51 (3H, m), 2.40-2.31 (1H, m), 2.23-2.14 (1H, m), 2.02-1.97 (2H, m), 1.92-1.86 (1H, m), 1.83-1.76 (1H, m), 1.57 (9H, s), 1.52 (9H, s), 1.47-1.40 (9H, m), 1.36 (3H, s), 1.30 (3H, s), 1.11-1.05 (2H, m), 1.02-0.96 (1H, m), 0.86 (3H, s).

LCMS: [M+H]⁺/Rt=787.62/4.14 min^(D)

Reference Example 53: tert-butyl 6-({1-[N²-(tert-butoxycarbonyl)-N-methyl-D-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 53-2 and methylamine hydrochloride as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (270 mg).

¹H-NMR (CD₃OD) δ: 7.32 (1H, d, J=8.6 Hz), 6.68 (1H, d, J=8.6 Hz), 5.14-5.07 (1H, m), 4.61-4.27 (5H, m), 4.00-3.91 (1H, m), 2.74-2.54 (6H, m), 2.49-2.41 (1H, m), 2.41-2.32 (1H, m), 2.23-2.14 (1H, m), 2.01-1.97 (1H, m), 1.92-1.86 (1H, m), 1.83-1.76 (1H, m), 1.57 (9H, s), 1.52 (9H, s), 1.46-1.40 (9H, m), 1.36 (3H, s), 1.30 (3H, s), 1.11-1.04 (2H, m), 1.01-0.95 (1H, m), 0.86 (3H, s).

LCMS: [M+H]⁺/Rt=800.73/4.09 min^(D)

Reference Example 54: tert-butyl 6-({1-[N²-(tert-butoxycarbonyl)-N,N-dimethyl-D-asparaginyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 53-2 and dimethylamine hydrochloride as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (251 mg).

¹H-NMR (CDCl₃) δ: 7.18 (1H, d, J=8.6 Hz), 6.36 (1H, d, J=8.6 Hz), 5.82-5.50 (1H, m), 4.94-4.86 (1H, m), 4.85-4.72 (1H, m), 4.64-4.53 (1H, m), 4.43-4.31 (2H, m), 4.26-4.19 (1H, m), 4.08-3.99 (1H, m), 2.99-2.84 (8H, m), 2.62-2.54 (2H, m), 2.34-2.25 (1H, m), 2.18-2.12 (1H, m), 2.02-1.98 (1H, m), 1.90-1.85 (1H, m), 1.83-1.75 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.40 (9H, s), 1.33 (3H, s), 1.26 (3H, s), 1.12-1.06 (2H, m), 1.03-0.99 (1H, m), 0.81 (3H, s).

LCMS: [M+H]⁺/Rt=814.69/4.15 min^(D)

Reference Example 55: tert-butyl 6-{[(3R)-1-{[(tert-butoxycarbonyl)amino](1H-imidazol-4-yl)acetyl}pyrrolidin-3-yl]oxy}-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Reference Example 55-1: benzyl (3R)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]pyrrolidine-1-carboxylate

Cyanomethylenetri-n-butylphosphorane (0.762 mL, 2.90 mmol) was added dropwise to a toluene solution (5 mL) of the compound of Reference Example 1-6 (500 mg, 0.968 mmol) and (S)-1-Cbz-3-pyrrolidinol (321 mg). The reaction solution was warmed up to 100° C., and stirred for 3 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10 to 65/35) to obtain the title compound (681 mg).

¹H-NMR (CDCl₃) δ: 7.29-7.25 (5H, m), 7.14 (1H, dd, J=8.5, 3.0 Hz), 6.60 (1H, dd, J=12.2, 8.5 Hz), 5.08-5.03 (2H, m), 4.82 (1H, s), 4.18-4.16 (1H, m), 3.69-3.45 (4H, m), 2.55-2.53 (2H, m), 2.26-2.23 (1H, m), 2.14-2.10 (2H, m), 1.96-1.94 (2H, m), 1.84-1.81 (1H, m), 1.76-1.72 (1H, m), 1.45-1.44 (18H, m), 1.29 (3H, s), 1.21 (3H, s), 1.05-1.03 (2H, m), 0.97 (1H, d, J=10.4 Hz), 0.76 (3H, s).

Reference Example 55-2: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[(3R)-pyrrolidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

10% palladium on carbon (340 mg) was added to a methanol (5 mL) solution of the compound of Reference Example 55-1 (681 mg, 0.945 mmol), and the reaction mixture was stirred for 5 hours under a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5 to 80/20) to obtain the title compound (333 mg).

LCMS: [M+H]⁺/Rt=586/0.990 min^(A)

Reference Example 55: tert-butyl 6-{[(3R)-1-{[(tert-butoxycarbonyl)amino](1H-imidazol-4-yl)acetyl}pyrrolidin-3-yl]oxy}-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 55-2 (86 mg, 0.138 mmol) as the starting material by the same method described in Reference Example 36-4 to obtain the title compound (90.7 mg).

LCMS: [M+H]⁺/Rt=809.53/0.874 min^(E)

Reference Example 56: tert-butyl 4-(1-[(tert-butoxycarbonyl)amino]-2-{(3S)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]pyrrolidin-1-yl}-2-oxoethyl)-1H-imidazole-1-carboxylate

Reference Example 56-1: benzyl (3S)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl)}phenoxy]pyrrolidine-1-carboxylate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-6 and (R)-1-Cbz-3-pyrrolidinol as the starting materials by the same method described in Reference Example 55-1 to obtain the title compound.

¹H-NMR (CDCl₃) δ: 7.30-7.21 (5H, in), 7.17-7.11 (1H, m), 6.60 (1H, dd, J=12.8, 8.5 Hz), 5.10-5.01 (2H, m), 4.83-4.80 (1H, m), 4.18-4.16 (1H, in), 3.69-3.45 (4H, m), 2.55-2.53 (2H, in), 2.28-2.21 (1H, m), 2.14-2.10 (2H, m), 1.95 (2H, t, J=5.5 Hz), 1.83-1.80 (1H, m), 1.76-1.72 (1H, m), 1.45-1.44 (18H, m), 1.29 (3H, s), 1.21 (3H, s), 1.05-1.03 (2H, m), 0.97 (1H, d, J=11.0 Hz), 0.76 (3H, s).

Reference Example 56-2: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{[(3S)-pyrrolidin-3-yl]oxy}-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 56-1 as the starting material by the same method described in Reference Example 55-2 to obtain the title compound.

LCMS: [M+H]⁺/Rt=586/0.993 min^(A)

Reference Example 56: tert-butyl 4-(1-[(tert-butoxycarbonyl)amino]-2-{(3S)-3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]pyrrolidin-1-yl)-2-oxoethyl)-1H-imidazole-1-carboxylate

A reaction, work-up, and purification were performed using the compound of Reference Example 56-2 (54 mg, 0.093 mmol) and [(tert-butoxycarbonyl)amino][1-(tert-butoxycarbonyl)-1H-imidazol-4-yl]acetic acid (38 mg, 0.11 mmol) as the starting materials by the same method described in Reference Example 55 to obtain the title compound (47 mg).

LCMS: [M+H]⁺/Rt=909.53/1.356 min^(E)

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and carboxylic acid corresponding to each of the following Reference Examples as the starting materials by the same method described in Reference Example 36-4 to obtain each of Reference Example compounds 57 to 62 shown in Tables 2-7 and 2-8.

TABLE 2-7 Reference Example Structural formula NMR and/or LCMS 57

LCMS: [M + H]⁺/Rt = 809.49/0.973 min^(C) 58

LCMS: [M + H]⁺/Rt = 707.43/1.187 min^(A) 59

LCMS: [M + H]⁺/Rt = 681.60/3.75 min^(D) ¹H-NMR (CDCl₃) δ: 7.66 (1H, s), 7.20 (1H, d, J = 8.0 Hz), 6.38 (1H, d, J = 8.6 Hz), 4.99-4.87 (1H, m), 4.55-4.49 (1H, m), 4.40- 4.34 (1H, m), 4.28-4.20 (1H, m), 4.12-4.06 (1H, m), 3.62-3.58 (2H, m), 2.63-2.54 (2H, m), 2.33-2.24 (1H, m), 2.21-2.10 (1H, m), 2.03-1.96 (1H, m), 1.90-1.84 (1H, m), 1.81- 1.74 (1H, m), 1.53-1.51 (18H, m), 1.34 (3H, s), 1.26 (3H, s), 1.11-1.07 (2H, m), 1.02- 0.98 (1H, m), 0.81 (3H, s). 60

¹H-NMR (CDCl₃) δ: 7.20 (2H, d, J = 8.5 Hz), 6.39 (1H, d, J = 8.5 Hz), 4.93-4.90 (1H, m), 4.42-4.31 (2H, m), 4.22 (1H, dd, J = 9.2, 1.8 Hz), 4.13-4.02 (2H, m), 3.59-3.55 (1H, m), 3.44-3.38 (1H, m), 3.29-3.25 (1H, m), 2.92-2.87 (1H, m), 2.59 (3H, t, J = 8.2 Hz), 2.35-2.23 (1H, m), 2.19-2.12 (3H, m), 2.09-2.02 (2H, m), 1.88-1.85 (1H, m), 1.78 (1H, d, J = 14.6 Hz), 1.54 (9H, s), 1.52 (18H, s), 1.43 (3H, s), 1.34 (3H, s), 1.09 (2H, t, J = 8.5 Hz), 1.01 (1H, d, J = 11.0 Hz), 0.82 (3H, s).

TABLE 2-8 61

¹H-NMR (CDCl₃) δ: 7.21 (1H, d, J = 8.5 Hz), 6.40 (1H, d, J = 8.5 Hz), 4.94-4.90 (1H, m), 4.70-4.30 (4H, m), 4.25 (1H, dd, J = 8.9, 2.1 Hz), 4.13-3.80 (6H, m), 3.01-2.75 (3H, m), 2.61 (2H, t, J = 8.2 Hz), 2.35- 2.28 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.92-1.87 (1H, m), 1.83-1.78 (1H, m), 1.56 (9H, s), 1.53 (9H, s), 1.47 (18H, s), 1.36 (3H, s), 1.27 (3H, s), 1.13 (2H, dt, J = 17.5, 6.3 Hz), 1.03 (1H, d, J = 11.0 Hz), 0.84 (3H, s) 62

LCMS: [M + H]⁺/Rt = 801.41/1.463 min^(C) ¹H-NMR (CD₃OD) δ: 7.31 (1H, d, J = 8.5 Hz), 6.69 (1H, dd, J = 8.5, 2.4 Hz), 5.30 (1H, s), 5.17 (1H, s), 5.08 (1H, s), 4.61 (1H, t, J = 7.6 Hz), 4.37 (1H, dd, J = 11.3, 6.4 Hz), 4.31-4.26 (3H, m), 4.18-4.14 (1H, m), 3.94 (1H, d, J = 11.6 Hz), 3.63 (1H, s), 3.55 (1H, s), 2.58 (2H, t, J = 7.9 Hz), 2.38-2.31 (2H, m), 2.20- 2.15 (2H, m), 1.98 (1H, t, J = 5.5 Hz), 1.89-1.85 (1H, m), 1.78 (1H, d, J = 14.6 Hz), 1.58 (9H, s), 1.52 (9H, s), 1.47 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.07 (2H, t, J = 8.2 Hz), 0.97 (1H, dd, J = 11.0, 1.8 Hz), 0.85 (3H, s).

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 3 to obtain each of Reference Example compounds 63 to 105 shown in Tables 2-9 to 2-16.

TABLE 2-9 Refe- rence Exam- ple Structural formula NMR and/or LCMS 63

LCMS: [M + H]⁺/Rt = 807.2/2.91 min^(B) ¹H-NMR (CDCl₃) δ: 8.63-8.57 (2H, m), 7.73-7.66 (1H, m), 7.34-7.29 (1H, m), 7.20 (1H, dd, J = 8.1 Hz, 5.4 Hz), 6.34 (1H, t, J = 8.1 Hz), 6.00-5.83 (1H, m), 5.24-5.17 (1H, m), 4.98-4.78 (1H, m), 4.64-4.42 (1H, m), 4.33-4.06 (3H, m), 4.04-3.82 (1H, m), 2.64- 2.56 (2H, m), 2.36-2.27 (1H, m), 2.21-2.12 (1H, m), 2.05-2.00 (1H, m), 1.91-1.77 (2H, m), 1.56-1.40 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.13-1.00 (3H, m), 0.83 (3H, s). 64

LCMS: [M + H]⁺/Rt = 810.0/2.93 min^(B) ¹H-NMR (CDCl₃) δ: 7.46-7.36 (2H, m), 7.22-7.18 (1H, m), 6.36-6.33 (1H, m), 5.67-5.50 (1H, m), 5.19- 5.15 (1H, m), 5.05-4.93 (1H, m), 4.85-4.63 (1H, m), 4.48-4.22 (3H, m), 4.16-3.95 (1H, m), 3.88-3.66 (3H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.19- 2.14 (1H, m), 2.05-2.00 (1H, m), 1.93-1.76 (2H, m), 1.56-1.41 (27H, m), 1.35 (3H, s), 1.28 (3H, s), 1.13- 1.00 (3H, m), 0.83 (3H, s). 65

LCMS: [M + H]⁺/Rt = 813.0/2.97 min^(B) ¹H-NMR (CDCl₃) δ: 8.15 (1H, br), 7.21 (1H, d, J = 8.1 Hz), 6.71 (1H, s), 6.41 (1H, d, J = 8.1 Hz), 5.00- 4.88 (1H, m), 4.54-4.49 (1H, m), 4.42-4.35 (1H, m), 4.31-4.23 (2H, m), 4.14-4.08 (1H, m), 3.49 (2H, s), 2.65-2.56 (2H, m), 2.36-2.26 (1H, m), 2.19-2.12 (1H, m), 2.06-2.00 (1H, m), 1.92-1.77 (2H, m), 1.61- 1.44 (27H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s) 66

LCMS: [M + H]⁺/Rt = 798.8/3.05 min^(B) ¹H-NMR (CDCl₃) δ: 7.82 (1H, br), 7.72 (1H, s), 7.23 (1H, d, J = 8.1 Hz), 6.45 (1H, d, J = 8.1 Hz), 4.97- 4.84 (2H, m), 4.56-4.52 (2H, m), 4.26-4.19 (2H, m), 2.65-2.59 (2H, m), 2.36-2.28 (1H, m), 2.22-2.14 (1H, m), 2.04-2.00 (1H, m), 1.91-1.76 (2H, m), 1.60- 1.49 (27H, m), 1.36 (3H, s), 1.28 (3H, s), 1.15-1.01 (3H, m), 0.84 (3H, s). 67

LCMS: [M + H]⁺/Rt = 1017.7/3.24 min^(B) ¹H-NMR (CDCl₃) δ: 7.47-7.18 (11H, m), 6.92-6.87 (3H, m), 6.36-6.26 (1H, m), 5.86-5.69 (1H, m), 5.19- 3.76 (11H, m), 2.63-2.57 (2H, m), 2.36-2.27 (1H, m), 2.18-2.13 (1H, m), 2.05-2.00 (1H, m), 1.89-1.77 (2H, m), 1.57-1.39 (27H, m), 1.35 (3H, s), 1.26 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s).

TABLE 2-10 68

LCMS: [M + H]′/Rt = 1017.9/3.36 min^(B) ¹H-NMR (CDCl₃) δ: 7.41-7.15 (12H, m), 6.61-6.53 (2H, m), 6.24-6.11 (1H, m), 5.66-5.49 (2H, m), 5.11-5.00 (4H, m), 4.81-3.72 (5H, m), 2.64-2.54 (2H, m), 2.36-2.28 (1H, m), 2.20-2.16 (1H, m), 2.09-2.00 (1H, m), 1.89-1.78 (2H, m), 1.68-1.23 (33H, m), 1.14-1.02 (3H, m), 0.83 (3H, s). 69

LCMS: [M + H]⁺/Rt = 681.39/3.96 min^(D) ¹H-NMR (CDCl₃) δ: 7.78 (1H, d, J = 1.1 Hz), 7.73 (1H, d, J = 1.1 Hz), 7.23-7.18 (1H, m), 6.37 (1H, d, J = 8.6 Hz), 5.09 (1H, d, J = 16.0 Hz), 5.01-4.91 (2H, m), 4.53-4.45 (1H, m), 4.45-4.37 (1H, m), 4.26-4.21 (1H, m), 4.19-4.07 (2H, m), 2.63-2.56 (2H, m), 2.34-2.25 (1H, m), 2.20-2.12 (1H, m), 2.03-1.98 (1H, m), 1.92-1.85 (1H, m), 1.83-1.75 (1H, m), 1.54 (9H, s), 1.52 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.12-1.07 (2H, m), 1.01 (1H, d, J = 11.5 Hz), 0.82 (3H, s). 70

LCMS: [M + H]⁺/Rt = 824.0/2.51 min^(B) ¹H-NMR (CDCl₃) δ: 7.39 (1H, s), 7.22 (1H, d, J = 8.1 Hz), 6.90 (1H, s), 6.41 (1H, d, J = 8.1 Hz), 4.93-4.61 (3H, m), 4.41-4.35 (1H, m), 4.27-4.23 (2H, m), 4.06-4.00 (2H, m), 3.52-3.37 (4H, m), 2.64-2.56 (2H, m), 2.36-2.27 (1H, m), 2.19-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.66 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.86 (3H, s). 71

LCMS: [M + H]⁺/Rt = 812.9/2.93 min^(B) ¹H-NMR (CDCl₃) δ: 8.77-8.76 (1H, m), 7.36-7.33 (1H, m), 7.22 (1H, d, J = 8.1 Hz), 6.39 (1H, d, J = 8.1 Hz), 5.98-5.92 (1H, m), 5.54-5.48 (1H, m), 5.01-4.87 (1H, m), 4.74-4.68 (1H, m), 4.48-4.03 (4H, m), 2.64-2.58 (2H, m), 2.36-2.27 (2H, m), 2.04-2.00 (1H, m), 1.92- 1.76 (2H, m), 1.57-1.52 (18H, m), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.01 (3H, m), 0.83 (3H, s). 72

LCMS: [M + H]⁺/Rt = 865.61/1.332 min^(E)

TABLE 2-11 73

¹H-NMR (400 MHz, CDCl₃) δ: 7.39-7.37 (6H, m), 7.27-7.12 (10H, m), 6.49 (1H, d, J = 8.5 Hz), 5.16-5.13 (1H, m), 4.92-4.90 (1H, m), 4.83-4.79 (2H, m), 4.24-4.20 (3H, m), 4.13-4.07 (1H, m), 2.64-2.56 (4H, m), 2.35-2.26 (1H, m), 2.19-2.13 (1H, m), 2.02-1.99 (1H, m), 1.90-1.86 (1H, m), 1.81-1.77 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.41 (9H, s), 1.34 (3H, s), 1.26 (3H, s), 1.11-1.00 (2H, m), 0.82 (3H, s). 74

LCMS: [M + H]⁺/Rt = 1045/1.347 min^(C) 75

LCMS: [M + H]⁺/Rt = 759.20/4.09 min^(D) ¹H-NMR (CDCl₃) δ: 7.22-7.17 (1H, m), 6.40-6.36 (1H, m), 5.58-5.41 (1H, m), 4.98-4.89 (1H, m), 4.76-4.53 (1H, m), 4.44-4.19 (3H, m), 4.13-4.02 (1H, m), 3.91- 3.80 (1H, m), 3.73-3.64 (1H, m), 2.62-2.55 (2H, m), 2.35-2.25 (1H, m), 2.19-2.11 (1H, m), 2.03-1.97 (1H, m), 1.92-1.84 (1H, m), 1.82-1.75 (1H, m), 1.54 (9H, s), 1.51 (9H, s), 1.44-1.40 (9H, m), 1.34 (3H, s), 1.26 (3H, s), 1.12-1.06 (2H, m), 1.03-0.99 (1H, m), 0.81 (3H, s). 76

LCMS: [M + H]⁺/Rt = 843.8/3.14 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 4.93 (1H, br), 4.79-4.67 (1H, m), 4.61- 4.48 (1H, m), 4.40-4.31 (2H, m), 4.25 (1H, dd, J = 8.1 Hz, 2.7 Hz), 4.14-4.05 (1H, m), 2.67-2.58 (4H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.04-2.00 (1H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46- 1.42 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 77

LCMS: [M + H]⁺/Rt = 814.7/2.89 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.77 (1H, br), 6.41 (1H, d, J = 8.1 Hz), 5.70-4.90 (2H, m), 4.75-4.04 (7H, m), 2.65-2.59 (2H, m), 2.36-2.28 (1H, m), 2.20-2.14 (1H, m), 2.04-2.00 (1H, m), 1.91-1.78 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36-1.23 (12H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE 2-12 78

LCMS: [M + H]⁺/Rt = 843.7/3.21 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 5.32-5.29 (1H, m), 5.00-4.84 (1H, m), 4.79-4.64 (1H, m), 4.59-4.48 (1H, m), 4.40-4.30 (2H, m), 4.27-4.23 (1H, m), 4.14-4.05 (1H, m), 2.67-2.56 (4H, m), 2.36-2.26 (1H, m), 2.22-2.13 (1H, m), 2.05- 2.00 (1H, m), 1.92-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45-1.40 (18H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 79

LCMS: [M + H]⁺/Rt = 785.7/1.40 min^(C) 80

LCMS: [M − Boc + H]⁺/Rt = 737.5/1.47 min^(C) 81

LCMS: [M + H]⁺/Rt = 787.7/1.40 min^(C) 82

LCMS: [M + H]⁺/Rt = 805.7/3.07 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.01-4.43 (3H, m), 4.37-4.30 (1H, m), 4.27-4.00 (3H, m), 3.85-3.75 (2H, m), 2.65-2.48 (4H, m), 2.36-2.27 (1H, m), 2.20-2.14 (1H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.59-1.45 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE 2-13 83

LCMS: [M + H]′/Rt = 797.3/3.07 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.97-4.89 (1H, m), 4.45-4.32 (2H, m), 4.27-4.23 (1H, m), 4.16-4.05 (2H, m), 2.96-2.71 (4H, m), 2.65-2.56 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.01 (5H, m), 1.92-1.67 (5H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 84

LCMS: [M + H]⁺/Rt = 769.8/3.03 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 4.99-4.93 (1H, m), 4.45-4.46 (1H, m), 4.40-4.34 (1H, m), 4.27-4.05 (3H, m), 3.60-3.26 (4H, m), 2.95-2.80 (1H, m), 2.65-2.59 (2H, m), 2.36-2.26 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (3H, m), 1.90- 1.76 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 85

LCMS: [M + H]⁺/Rt = 797.8/3.18 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.00-4.82 (1H, m), 4.48-4.08 (7H, m), 3.40-3.12 (1H, m), 2.64-2.58 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-1.76 (5H, m), 1.60-1.56 (15H, m), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 86

LCMS: [M + H]⁺/Rt = 783.9/3.09 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.96-4.86 (1H, m), 4.37-4.00 (6H, m), 3.37-3.26 (2H, m), 2.80-2.58 (4H, m), 2.36-2.26 (1H, m), 2.20-2.13 (1H, m), 2.09-1.77 (7H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 87

LCMS: [M + H]⁺/Rt = 783.8/3.22 min^(B) ¹H-NMR (CDCl₃) δ: 7.21 (1H, d, J = 8.1 Hz), 6.39-6.33 (1H, m), 4.94-4.68 (2H, m), 4.55-3.89 (7H, m), 2.64- 2.56 (2H, m), 2.36-2.27 (1H, m), 2.27-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.70-1.23 (39H, m), 1.13-1.01 (3H, m), 0.83 (3H, s). 88

LCMS: [M + H]⁺/RT = 783.9/3.11 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.51-4.04 (8H, m), 2.85-2.56 (3H, m), 2.36-2.14 (3H, m), 2.05-2.00 (1H, m), 1.93-1.77 (3H, m), 1.74-1.44 (30H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE 2-14 89

LCMS: [M + H]′/Rt = 783.6/3.05 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 4.99-4.92 (1H, m), 4.51-4.45 (1H, m), 4.39-4.32 (1H, m), 4.27-4.04 (5H, m), 2.80-2.53 (3H, m), 2.36-2.25 (2H, m), 2.20-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.71-1.51 (23H, m), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 90

LCMS: [M + H]⁺/Rt = 670.7/2.88 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 4.97-4.90 (1H, m), 4.76-4.63 (1H, m), 4.47-4.22 (4H, m), 4.14-4.05 (1H, m), 3.92-3.81 (2H, m), 2.64-2.58 (2H, m), 2.36-2.27 (1H, m), 2.21-2.11 (3H, m), 2.05-2.00 (1H, m), 1.95-1.79 (4H, m), 1.62- 1.54 (18H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 91

LCMS: [M + H]⁺/Rt = 845.8/3.14 min^(B) ¹H-NMR (CDCl₃) δ: 7.32-7.20 (6H, m), 6.42 (1H, d, J = 8.1 Hz), 5.05-4.86 (1H, m), 4.64-3.91 (7H, m), 3.49- 3.26 (2H, m), 2.64-2.58 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (2H, m), 2.08-2.00 (2H, m), 1.96-1.78 (2H, m), 1.56-1.45 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 92

LCMS: [M + H]⁺/Rt = 781.7/3.07 min^(B) ¹H-NMR (CDCl₃) δ: 7.21 (1H, d, J = 8.1 Hz), 6.39 (1H, d, J = 8.1 Hz), 4.97-4.86 (1H, m), 4.78-4.33 (3H, m), 4.26-3.98 (3H, m), 3.50-3.42 (1H, m), 2.64-2.58 (2H, m), 2.41-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00(2H, m), 1.96-1.77 (2H, m), 1.56-1.41 (29H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (4H, m), 0.96-0.69(4H, m). 93

LCMS: [M + H]⁺/Rt = 684.0/2.18 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.67-4.57 (1H, m), 4.47-4.36 (1H, m), 4.27-4.23 (2H, m), 4.15-4.05 (1H, m), 3.25-2.94 (1H, m), 2.64-2.58 (2H, m), 2.47-2.27 (5H, m), 2.21-2.14 (2H, m), 2.05-2.00 (1H, m), 1.97-1.66 (6H, m), 1.56 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 94

LCMS: [M + H]⁺/Rt = 797.9/3.23 min^(B) ¹H-NMR (CDCl₃) δ: 7.21 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.97-4.89 (1H, m), 4.47-4.33 (2H, m), 4.26-4.23 (1H, m), 4.16-4.03 (4H, m), 3.87-3.77 (2H, m), 2.65-2.58 (2H, m), 2.36-2.28 (1H, m), 2.21-2.12 (1H, m), 2.08-1.78 (10H, m), 1.60-1.44 (27H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

TABLE 2-15 95

LCMS: [M + H]⁺/Rt = 799.9/3.01 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 4.95-4.88 (1H, m), 4.56-4.32 (2H, m), 4.26-3.81 (6H, m), 3.57-3.48 (1H, m), 2.93-2.80 (1H, m), 2.71-2.58 (3H, m), 2.36-2.26 (2H, m), 2.22-2.10 (2H, m), 2.04-2.00 (2H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.46 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 96

LCMS: [M + H]⁺/Rt = 769.9/2.98 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.98-4.91 (1H, m), 4.47-4.41 (1H, m), 4.37-4.31 (1H, m), 4.27-4.23 (1H, m), 4.18-4.02 (4H, m), 3.61-3.55 (2H, m), 2.98-2.85 (1H, m), 2.65-2.59 (2H, m), 2.42 (2H, d, J = 8.1 Hz), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.76 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.43 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 97

LCMS: [M + H]⁺/Rt = 898.9/3.14 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.24-5.07 (1H, m), 5.02-4.90 (1H, m), 4.55-4.00 (6H, m), 3.62-2.92 (5H, m), 2.65-2.59 (2H, m), 2.49-2.23 (2H, m), 2.22-2.12 (1H, m), 2.05-2.00 (1H, m), 1.95-1.78 (3H, m), 1.58-1.42 (36H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 98

LCMS: [M + H]⁺/Rt = 798.0/3.10 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 4.96-4.89 (1H, m), 4.49-4.32 (2H, m), 4.27-4.23 (1H, m), 4.16-4.02 (3H, m), 3.89-3.75 (1H, m), 3.33-3.26 (1H, m), 2.65-2.58 (2H, m), 2.36-2.28 (1H, m), 2.22-2.07 (3H, m), 2.05-2.00 (2H, m), 1.97-1.78 (7H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 99

LCMS: [M + H]⁺/Rt = 912.7/3.1 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.13-5.09 (1H, m), 5.00-4.91 (1H, m), 4.75-4.69 (1H, m), 4.54-3.99 (8H, m), 2.70-2.59 (4H, m), 2.36-2.28 (1H, m), 2.23-2.13 (1H, m), 2.05-2.00 (1H, m), 1.94-1.87 (1H, m), 1.84-1.62 (4H, m), 1.60- 1.53 (18H, m), 1.45-1.42 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 100

LCMS: [M + H]⁺/Rt = 783.7/2.99 min^(B)

TABLE 2-16 101

LCMS: [M + H]⁺/Rt = 783.6/3.01 min^(B) 102

LCMS: [M + H]⁺/Rt = 783.9/3.08 min^(B) 103

LCMS: [M + H]⁺/Rt = 783.8/3.08 min^(B) 104

LCMS: [M + H]⁺/Rt = 797.9/3.17 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.42 (1H, d, J = 8.1 Hz), 4.97-4.89 (1H, m), 4.68-4.40 (2H, m), 4.36-3.94 (5H, m), 2.87-2.69 (1H, m), 2.63-2.53 (2H, m), 2.47-2.13 (4H, m), 2.04-2.00 (1H, m), 1.93-1.77 (2H, m), 1.68-1.54 (24H, m), 1.46-1.45 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 105

LCMS: [M + H]⁺/Rt = 794.6/2.90 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 5.00-4.85 (1H, m), 4.61-3.92 (7H, m), 3.67-3.56 (1H, m), 3.50-2.98 (1H, m), 2.64-2.46 (3H, m), 2.41-2.13 (3H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.59-1.54 (18H, m), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 as the starting material by the same method described in Reference Example 41 to obtain each of Reference Example compounds 106 to 108 shown in Table 2-17.

TABLE 2-17 Reference Example Structural formula NMR and/or LCMS 106

LCMS: [M + H]⁺/Rt = 702.8/2.72 min^(B) ¹H-NMR (CDCl₃) δ: 10.51 (1H, br), 7.62 (1H, s), 7.56 (1H, s), 7.18 (1H, d, J = 8.1 Hz), 6.30 (1H, d, J = 8.1 Hz), 4.76- 4.71 (1H, m), 4.33-4.22 (3H, m), 4.01- 3.96 (2H, m), 2.62-2.56 (2H, m), 2.36- 2.27 (1H, m), 2.19-2.13 (1H, m), 2.04- 2.00 (1H, m), 1.92-1.76 (2H, m), 1.53 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.26 (3H, s), 1.11-1.00 (3H, m), 0.83 (3H, s). 107

LCMS: [M + H]⁺/Rt = 714.0/2.96 min^(B) ¹H-NMR (CDCl₃) δ: 9.07 (1H, d, J = 2.7 Hz), 8.88 (1H, dd, J = 5.4 Hz, 2.7 Hz), 8.15-8.11 (1H, m), 7.53 (1H, dd, J = 8.1 Hz, 5.4 Hz), 7.18 (1H, d, J = 8.1 Hz), 6.37 (1H, d, J = 8.1 Hz), 4.86-4.82 (1H, m), 4.27-4.21 (3H, m), 3.87-3.82 (2H, m), 2.62-2.56 (2H, m), 2.35-2.27 (1H, m), 2.19-2.12 (1H, m), 2.03-1.99 (1H, m), 1.91-1.76 (2H, m), 1.52 (9H, s), 1.49 (9H, s), 1.35 (3H, s), 1.26 (3H, s), 1.11- 0.99 (3H, m), 0.83 (3H, s). 108

LCMS: [M + H]⁺/Rt = 729.8/2.84 min^(B) ¹H-NMR (CDCl₃) δ: 8.23 (1H, d, J = 8.1 Hz), 7.99 (1H, dd, J = 8.1 Hz, 2.7 Hz), 7.46-7.31 (2H, m), 7.20 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 4.99-4.90 (1H, m), 4.60-4.54 (2H, m), 4.42-4.36 (2H, m), 4.24 (1H, dd, J = 8.1 Hz, 2.7 Hz), 2.64-2.56 (2H, m), 2.36-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.76 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.35 (3H, s), 1.28 (3H, s), 1.13- 1.00 (3H, m), 0.83 (3H, s).

A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 as the starting material by the same method described in Reference Example 42 to obtain each of Reference Example compounds 109 to 113 shown in Table 2-18.

TABLE 2-18 Reference Example Structural formula NMR and/or LCMS 109

LCMS: [M + H]⁺/Rt = 786.9/2.77 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.41-6.37 (1H, m), 6.02 (1H, br), 5.71- 5.61 (1H, m), 5.48-5.39 (1H, m), 4.95-4.89 (1H, m), 4.75-4.50 (2H, m), 4.42-4.32 (2H, m), 4.27-4.23 (1H, m), 4.10-4.03 (1H, m), 2.73-2.54 (4H, m), 2.36-2.27 (1H, m), 2.20-2.13 (1H, m), 2.04-2.00 (1H, m), 1.92- 1.77 (2H, m), 1.57 (9H, s), 1.53 (9H, s), 1.43 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.83 (3H, s). 110

LCMS: [M + H]⁺/Rt = 671.6/2.59 min^(B) ¹H-NMR (CDCl₃) δ: 7.32 (1H, d, J = 8.1 Hz), 6.70 (1H, d, J = 8.2 Hz), 5.12-5.06 (1H, m), 4.68-4.62 (1H, m), 4.40-4.17 (3H, m), 3.96-3.90 (1H, m), 2.60-2.49 (4H, m), 2.45-2.31 (3H, m), 2.23-2.11 (1H, m), 2.01-1.97 (1H, m), 1.90-1.66 (2H, m), 1.56 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.20-0.96 (3H, m), 0.86 (3H, s). 111

LCMS: [M + H]⁺/Rt = 800.8/2.72 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43-6.39 (1H, m), 5.01-4.91 (1H, m), 4.69-4.02 (6H, m), 2.64-2.58 (2H, m), 2.36-1.76 (9H, m), 1.61-1.53 (18H, m), 1.43-1.42 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 112

LCMS: [M + H]⁺/Rt = 800.7/2.81 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 6.23-6.16 (1H, m), 5.56-5.40 (1H, m), 5.00-4.92 (1H, m), 4.75-4.65 (1H, m), 4.56-4.23 (4H, m), 4.12-4.03 (1H, m), 3.67-3.27 (2H, m), 2.64- 2.58 (2H, m), 2.37-2.27 (1H, m), 2.22-2.12 (1H, m), 2.04-1.98 (4H, m), 1.93-1.77 (2H, m), 1.60-1.54 (18H, m), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 113

LCMS: [M + H]⁺/Rt = 801.7/2.70 min^(B) ¹H-NMR (CDCl₃) δ: 7.26-7.21 (1H, m), 6.43 (1H, d, J = 8.1 Hz), 6.25 (1H, br), 5.30-4.95 (2H, m), 4.75-4.52 (3H, m), 4.44-4.05 (5H, m), 3.74-3.15 (2H, m), 2.63-2.57 (2H, m), 2.37-2.28 (1H, m), 2.23-2.13 (1H, m), 2.05-2.01 (1H, m), 1.93-1.77 (2H, m), 1.57 (9H, s), 1.52 (9H, s), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.01 (3H, m), 0.84 (3H, s).

A reaction, work-up, and purification were performed using the compound of Reference Example 43-2 as the starting material by the same method described in Reference Example 43 to obtain each of Reference Example compounds 114 to 116 shown in Table 2-19.

TABLE 2-19 Refe- ence Exam- ple Structural formula NMR and/or LCMS 114

LCMS: [M + H]⁺/Rt = 824.58/4.36 min^(D) ¹H-NMR (CDCl₃) δ: 7.76-7.65 (1H, m), 7.24 (1H, d, J = 8.6 Hz), 6.41 (1H, d, J = 8.6 Hz), 5.11-5.04 (1H, m), 5.02-4.96 (1H, m), 4.95-4.89 (1H, m), 4.60-4.48 (3H, m), 4.47- 4.40 (1H, m), 4.31-4.20 (2H, m), 4.19-4.11 (1H, m), 2.92 (3H, s), 2.63 (2H, t, J = 8.3 Hz), 2.38-2.29 (1H, m), 2.23-2.14 (1H, m), 2.07- 2.01 (1H, m), 1.94-1.88 (1H, m), 1.86-1.78 (1H, m), 1.58 (9H, s), 1.55 (9H, s), 1.48 (9H, s), 1.37 (3H, s), 1.30 (3H, s), 1.13 (2H, t, J = 8.3 Hz), 1.04 (1H, d, J = 10.9 Hz), 0.85 (3H, s). 115

LCMS: [M + H]⁺/Rt = 879.59/3.24 min^(D) ¹H-NMR (CDCl₃) δ: 7.72 (1H, s), 7.40-7.17 (1H, m), 6.48-6.36 (1H, m), 5.12-4.87 (3H, m), 4.62-4.51 (1H, m), 4.49-4.36 (1H, m), 4.30- 4.21 (2H, m), 4.19-4.09 (1H, m), 3.74-3.65 (2H, m), 3.51-3.37 (4H, m), 2.67-2.56 (2H, m), 2.54-2.41 (4H, m), 2.36-2.26 (1H, m), 2.21- 2.12 (1H, m), 2.06-1.99 (1H, m), 1.94-1.75 (2H, m), 1.62-1.42 (27H, m), 1.38-1.35 (3H, m), 1.30-1.27 (3H, m), 1.14-1.08 (2H, m), 1.06-1.00 (1H, m), 0.86-0.82 (3H, m). 116

LCMS: [M + H]⁺/Rt = 725.50/3.77 min^(D) ¹H-NMR (CDCl₃) δ: 7.62 (1H, s), 7.22 (1H, d, J = 8.6 Hz), 6.38 (1H, d, J = 8.6 Hz), 5.10-4.90 (3H, m), 4.53-4.39 (2H, m), 4.28-4.22 (1H, m), 4.16-4.04 (2H, m), 3.98-3.82 (2H, m), 2.96 (2H, t, J = 5.7 Hz), 2.65-2.56 (3H, m), 2.37-2.26 (1H, m), 2.21-2.12 (1H, m), 2.04-2.00 (1H, m), 1.94-1.88 (1H, m), 1.86- 1.74 (1H, m), 1.57 (9H, s), 1.54 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.13-1.08 (2H, m), 1.03 (1H, d, J = 10.9 Hz), 0.84 (3H, s).

Reference Example 117: tert-butyl (4R)-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S, 7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}-4-hydroxypyrrolidine-1-carboxylate

Palladium on carbon (20 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (2 mL)(this is referred to as “solution A”). Meanwhile, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (94.1 mg, 0.340 mmol) was added to a DMF-methanol (2:1) mixture solution (3 mL) of trans-N-(tert-butoxycarbonyl)-4-hydroxy-L-proline (98.3 mg, 0.425 mmol), and the reaction mixture was stirred for 20 minutes at room temperature. The aforementioned solution A was then added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (222 mg).

¹H-NMR. (CDCl₃) δ: 7.22 (1H, d, J=8.1 Hz), 6.41 (1H, d, J=8.1 Hz), 4.99-4.89 (1H, m), 4.58-3.99 (7H, m), 3.69-3.42 (2H, m), 2.65-2.58 (2H, m), 2.36-2.26 (1H, m), 2.22-2.07 (3H, m), 2.05-2.00 (1H, m), 1.93-1.73 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45-1.44 (9H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=785.8/2.79 min^(B)

A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 as the starting material by the same method described in Reference Example 117 to obtain each of Reference Example compounds 118 to 119 shown in Table 2-20.

TABLE 2-20 Reference Example Structural formula NMR and/or LCMS 118

LCMS: [M + H]⁺/Rt = 785.8/2.94 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 5.14- 4.94 (2H, m), 4.57-4.03 (6H, m), 3.65- 3.42 (2H, m), 2.65-2.59 (2H, m), 2.36- 2.14 (3H, m), 2.04-1.76 (4H, m), 1.61- 1.42 (27H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 119

LCMS: [M + H]⁺/Rt = 785.8/2.87 min^(B) ¹H-NMR (CDCl₃) δ: 8.65 (1H, br), 7.22 (1H, d, J = 8.1 Hz), 6.43 (1H, d, J = 8.1 Hz), 5.00-4.88 (1H, m), 4.59- 4.05 (7H, m), 3.62-3.43 (2H, m), 2.64- 2.56 (2H, m), 2.36-2.26 (1H, m). 2.19- 2.00 (4H, m), 1.92-1.77 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

Reference Example 120: tert-butyl (2S,4S)-4-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S, 7aR)-3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

Reference Example 120-1: tert-butyl (2S,4S)-4-azido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

Palladium on carbon (40 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (6 mL) of the compound of Reference Example 1-7 (400 mug, 0.567 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (6 mL). cis-4-azido-(tert-butoxycarbonyl)-L-proline (160 mg, 0.624 mmol), HATU (259 mg, 0.680 mmol), and triethylamine (236 μL, 1.70 mmol) were added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (392 mg) as a colorless amorphous compound.

¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J=8.1 Hz), 6.40 (1H, d, J=8.1 Hz), 5.00-4.89 (1H, m), 4.82-4.01 (7H, m), 3.86-3.76 (1H, m), 3.39-3.32 (1H, m), 2.64-2.58 (2H, m), 2.48-2.28 (2H, m), 2.22-2.14 (1H, m), 2.04-2.00 (1H, m), 1.93-1.77 (3H, m), 1.56 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=810.8/3.02 min^(B)

Reference Example 120: tert-butyl (2S,4S)-4-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl)pyrrolidine-1-carboxylate

Palladium on carbon (40 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (5 mL) of the compound of Reference Example 120-1 (392 mg, 0.484 mmol), and the reaction mixture was stirred for 3 hours under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated. The residue was dissolved in acetonitrile (10 mL) and further filtered through cellulose. The filtered substance was washed with acetonitrile and the combined filtrate was concentrated to obtain the title compound (355 mg) as a brown solid.

¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J=8.1 Hz), 6.41 (1H, d, J=8.1 Hz), 5.00-4.89 (2H, m), 4.52-4.02 (5H, m), 3.68-3.49 (2H, m), 3.33-3.29 (1H, m), 2.64-2.61 (2H, m), 2.36-2.26 (2H, m), 2.20-2.14 (1H, m), 2.04-2.01 (1H, m), 1.93-1.73 (3H, m), 1.61 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=785.0/2.28 min^(B)

Reference Example 121: tert-butyl (2S,4S)-4-acetamido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

Triethylamine (101 μL, 0.727 mmol) and acetyl chloride (19 μL, 0.267 mmol) were added to a THE solution (2.4 mL) of the compound of Reference Example 120 (190 mg, 0.242 mmol), and the reaction mixture was stirred for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain the title compound (204 mg) as a colorless amorphous compound.

¹H-NMR (CDCl₃) δ: 8.38-8.23 (1H, m), 7.23 (1H, d, J=8.1 Hz), 6.43 (1H, d, J=8.1 Hz), 5.12-4.93 (2H, m), 4.72-4.63 (1H, m), 4.53-4.46 (1H, m), 4.32-4.02 (4H, m), 3.61-3.45 (2H, m), 2.65-2.59 (2H, m), 2.37-2.27 (2H, m), 2.21-2.14 (1H, m), 2.04-2.00 (1H, m), 1.98-1.78 (6H, m), 1.57 (9H, s), 1.54 (9H, s), 1.46-1.43 (9H, m), 1.36 (3H, s), 1.26 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=827.0/2.86 min$

Reference Example 122: tert-butyl (2S,4R)-4-amino-2-{3-(2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl)ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

Reference Example 122-1: tert-butyl (2S,4R)-4-azido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

Palladium on carbon (40 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (6 mL) of the compound of Reference Example 1-7 (400 mug, 0.567 mmol), and the reaction mixture was stirred for 30 minutes under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methylene chloride, and the combined filtrate was concentrated. The resulting residue was dissolved in DMF (6 mL). (2S,4R)-4-azido-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (189 mg, 0.737 mmol), HATU (259 mg, 0.680 mmol), and triethylamine (236 μL, 1.70 mmol) were added, and the reaction mixture was stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (397 mg) as a colorless amorphous compound.

¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J=8.1 Hz), 6.41 (1H, d, J=8.1 Hz), 5.00-4.00 (8H, m), 3.75-3.45 (2H, m), 2.74-2.58 (2H, m), 2.36-2.12 (4H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.60-1.54 (18H, m), 1.46-1.44 (9H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=810.7/3.05 min^(B)

Reference Example 122: tert-butyl (2S,4R)-4-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

A reaction, work-up, and purification were performed using the compound of Reference Example 122-1 (397 mg, 0.490 mmol) as the starting material by the same method described in Reference Example 120 to obtain the title compound (368 mg) as a colorless amorphous compound.

¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J=8.1 Hz), 6.40 (1H, d, J=8.1 Hz), 5.50-3.50 (9H, m), 3.26-3.07 (1H, m), 2.74-2.58 (2H, m), 2.36-2.28 (1H, m), 2.22-2.00 (3H, m), 1.92-1.77 (3H, m), 1.60-1.54 (18H, m), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.17-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=784.8/2.27 min^(B)

Reference Example 123: tert-butyl (2S,4R)-4-acetamido-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidine-1-carbonyl}pyrrolidine-1-carboxylate

A reaction, work-up, and purification were performed using the compound of Reference Example 122 (181 mg, 0.232 mmol) as the starting material by the same method described in Reference Example 121 to obtain the title compound (162 mg) as a colorless amorphous compound.

¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J=8.1 Hz), 6.42 (1H, d, J=8.1 Hz), 5.63-5.49 (1H, m), 5.00-3.94 (8H, m), 3.81-3.70 (1N, m), 3.48-3.32 (1H, m), 2.64-2.58 (2H, m), 2.36-2.14 (4H, m), 2.05-2.00 (1H, m), 1.98 (3H, s), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.54 (9H, s), 1.47-1.43 (9H, m), 1.36 (3H, S), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=826.7/2.81 min^(B)

Reference Example 124: tert-butyl (2S,4R)-4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-2-(dimethylcarbamoyl) pyrrolidine-1-carboxylate

Reference Example 124-1: benzyl (2S)-2-(dimethylcarbamoyl)-4-oxopyrrolidine-1-carboxylate

Triethylamine (0.48 mL, 3.44 mmol), HATU (873 mg, 2.30 mmol), and aqueous dimethylamine solution (about 9.5 mol/L, 0.24 mL, 2.3 mmol) were added to a THP solution (5.7 mL) of (2S)-1-benzyloxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (302 mg, 1.15 mmol) while cooling with ice, and the reaction mixture was stirred for 8 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (285 mg) as a colorless oily compound.

LCMS: [M+H]⁺/Rt=291.14/0.582 min^(A)

Reference Example 124-2: benzyl (2S)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethylidene) pyrrolidine-1-carboxylate

An n-butyl lithium/hexane solution (1.57 mol/L, 1.38 mL, 2.16 mmol) was slowly added to a THF solution (4.9 mL) of ethyl dimethylphosphonoacetate (423 mg, 2.16 mmol) at 78° C., and the reaction mixture was stirred for 30 minutes. A THF solution (4 ml) of the compound of Reference Example 124-1 (285 mg, 0.983 mmol) was added to the reaction solution at −78° C., and the reaction mixture was stirred for 5 hours at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (190 mg) as a colorless oil.

LCMS: [M+H]⁺/Rt=361.19/0.757 min^(A), 361.19/0.795 min^(A) (E/Z isomer mixture)

Reference Example 124-3: ethyl[(3R,5S)—S-(dimethylcarbamoyl)pyrrolidin-3-yl]acetate

A palladium on carbon-ethylenediamine complex (180 mg, Pd content: 10%, wetted with ca. 55t water) was added to a methanol solution (3.8 mL) of the compound of Reference Example 124-2 (190 mg, 0.526 mmol), and the reaction mixture was stirred for 7.5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite. The filtered substance was washed with methanol, and the combined filtrate was concentrated to obtain the title compound (116.3 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 4.05 (2H, q, J=7.1 Hz), 3.89 (1H, t, J=7.9 Hz), 3.02 (1H, dd, J=10.4, 6.7 Hz), 2.94 (3H, s), 2.91 (3H, s), 2.76 (1H, dd, J=10.4, 7.3 Hz), 2.57-2.48 (1H, m), 2.38-2.30 (3H, m), 2.23 (1H, dd, J=15.9, 7.9 Hz), 1.18 (3H, t, J=7.0 Hz).

LCMS: [M+H]⁺/Rt=229.12/0.244 min^(A)

Reference Example 124-4: tert-butyl (2S,4R)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate

Sodium hydrogen carbonate (128 mg, 1.53 mmol) and di-tert-butyl dicarbonate (0.237 mL, 1.02 mmol) were added to a THF-water (1:1) mixture solution (3 mL) of the compound of Reference Example 124-3 (116 mg, 0.509 mmol), and the reaction mixture was stirred for 14 hours at room temperature. The reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (125 mg) as a colorless oil.

¹H-NMR (CDCl₁) δ: 5.25 (1H, s), 4.00-3.94 (1H, m), 3.78-3.72 (1H, m), 3.76 (3H, s), 3.17 (1H, s), 1.46 (3H, s), 1.43 (9H, S).

Reference Example 124-5: [(3R,5S)-1-(tert-butoxycarbonyl)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetic acid

An aqueous 2 N sodium hydroxide solution (0.38 mL, 0.76 mmol) was added to a THF-water (2:1) mixture solution (1.8 mL) of the compound of Reference Example 124-4 (125 mg, 0.380 mmol) while cooling with ice, and the reaction mixture was stirred for 16 hours at room temperature. 1 N hydrochloric acid was added to the reaction solution, which was extracted with chloroform. The organic phase was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated to obtain the title compound (114 mg) as a white solid.

¹H-NMR (CDCl₃) δ: 4.54 (1H, dt, J=38.8, 7.9 Hz), 3.82-3.73 (1H, m), 3.11 (1H, td, J=9.6, 4.9 Hz), 3.04-2.97 (3H, m), 2.91 (3H, s), 2.54-2.35 (3H, m), 1.60-1.50 (2H, m), 1.35 (9H, d, J=23.3 Hz).

Reference Example 124: tert-butyl (2S,4R)-4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-2-(dimethylcarbamoyl) pyrrolidine-1-carboxylate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (145 mg, 0.253 mmol) and the compound of Reference Example 124-5 (114 mg, 0.380 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (167 mg) as a colorless amorphous compound.

LCMS: [M+H]⁺/RT=854.45/1.398 min^(C)

Reference Example 125: tert-butyl (2R,4S)-4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate

Reference Example 125-1. tert-butyl (2R)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate

A reaction, work-up, and purification were performed using tert-butyl (R)-2-(dimethylcarbamoyl)-4-oxopyrrolidine-1-carboxylate (325 mg, 1.27 mmol) as the starting material by the same method described in Reference Example 124-2 to obtain the title compound (167 mg) as a colorless oil.

LCMS: [M+H]⁺/Rt=327.24/0.704 min^(A), 327.24/0.748 min^(A) (two peaks detected due to being an E/Z isomer mixture)

Reference Example 125-2: tert-butyl (2R,4S)-2-(dimethylcarbamoyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate

A reaction and work-up were performed using the compound of Reference Example 125-1 (167 mg, 0.511 mmol) was used as the starting material by the same method described in Reference Example 124-3 to obtain the title compound (128 mg) as a colorless oil.

LCMS: [M+H]⁺/Rt=329.18/0.681 min^(A)

Reference Example 125-3: [(3S,5R)-1-(tert-butoxycarbonyl)-5-(dimethylcarbamoyl) pyrrolidin-3-yl]acetic

A reaction and work-up were performed using the compound of Reference Example 125-2 (128 mg, 0.388 mmol) as the starting materials by the same method described in Reference Example 124-4 to obtain the title compound (117 mg) as a white solid.

¹H-NMR (CDCl₃) δ: 4.55 (1H, dt, J=39.1, 7.9 Hz), 3.82-3.73 (1H, m), 3.10 (1H, dd, J m 11.3, 7.6 Hz), 3.02 (3H, d, J=16.4 Hz), 2.91 (3H, d, J=1.2 Hz), 2.52-2.39 (3H, m), 1.60-1.50 (2H, m), 1.35 (9H, d, J=23.2 Hz).

Reference Example 125: tert-butyl (2R,4S)-4-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (149 mg, 0.260 mmol) and the compound of Reference Example 125-3 (116 mg, 0.386 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (153 mg) as a colorless amorphous compound.

LCMS: [M+H]⁺/RT=854.47/1.398 min^(C)

Reference Example 126: tert-butyl 2-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1,1-dioxo-1λ⁶-thiomorpholine-4-carboxylate

Reference Example 126-1: [4-(tert-butoxycarbonyl)-1,1-dioxo-1λ⁶-thiomorpholin-2-yl]acetic acid

An aqueous 2 N sodium hydroxide solution (1.15 mL, 2.31 mmol) was added to a methanol solution (7 mL) of tert-butyl 2-(2-ethoxy-2-oxoethyl)thiomorpholine-4-carboxylate 1,1-dioxide (247 mg, 0.769 mmol) while cooling with ice, and the reaction mixture was stirred for 4.5 hours at room temperature. An aqueous 2 N sodium hydroxide solution (1.15 mL, 2.31 mmol) was further added, and the reaction mixture was stirred for 2 hours. 1 N hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated to obtain the title compound (225 mg) as a light yellow oily compound.

LCMS: [M+H]⁺/RT=292.13/0.521 min^(C)

Reference Example 126: tert-butyl 2-(2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1,1-dioxo-1λ⁶-thiomorpholine-4-carboxylate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 (0.30 g, 0.493 mmol) and the compound of Reference Example 126-1 (159 mg, 0.543 mmol) as the starting materials by the same method described in Reference Example 36-4 to obtain the title compound (225 mg) as a light yellow oil.

¹H-NMR (CDCl₁) 5: 7.22 (1H, d, J=8.7 Hz), 6.40 (1H, d, J=8.7 Hz), 4.97-4.91 (1H, m), 4.56-4.35 (3H, m), 4.31-4.16 (5H, m), 4.09-3.98 (2H, m), 3.05-3.00 (2H, m), 2.79 (1H, d, J=16.0 Hz), 2.62 (2H, t, J=8.2 Hz), 2.35-2.28 (1H, m), 2.22-2.15 (1H, m), 2.04-2.00 (1H, m), 1.95-1.85 (2H, m), 1.81 (1H, d, J=14.6 Hz), 1.56 (9H, s), 1.54 (9H, s), 1.47 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.11 (2H, t, J=8.2 Hz), 1.03 (1H, d, J=11.0 Hz), 0.83 (3H, s).

Reference Example 127: tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-{([1-(1H-imidazole-2-carbonyl)azetidin-3-yl]oxy)-3-(2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) as the starting material by the same method described in Reference Example 40 to obtain the title compound (119 mg).

¹H-NMR (CDCl₃) δ: 10.76 (1H, br), 7.23 (1H, d, J=8.1 Hz), 7.19 (1H, s), 7.13 (1H, s), 6.46 (1H, d, J=8.1 Hz), 5.15-4.99 (2H, m), 4.76-4.70 (1H, m), 4.60-4.54 (1H, m), 4.29-4.23 (2H, m), 2.65-2.59 (2H, m), 2.36-2.26 (1H, m), 2.23-2.14 (1H, m), 2.05-2.01 (1H, m), 1.93-1.78 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.36 (3H, s), 1.29 (3H, s), 1.15-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=666.9/2.83 min^(B)

Reference Example 128: N²-(tert-butoxycarbonyl)-N-[(2R)-1-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-serinamide

Reference Example 128-1: benzyl N-(tert-butoxycarbonyl)-D-seryl-D-alaninate

4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (809 mg, 2.92 mmol), triethylamine (0.355 mL, 2.56 mmol), and D-alanine benzyl p-toluenesulfonate (899 mg, 2.56 mmol) were added to a methanol (24 mL) solution of N-(tert-butoxycarbonyl)-D-serine (500 mg, 2.44 mmol), and the reaction mixture was stirred for 13 hours at room temperature. Water was added to the reaction solution, which was extracted with methylene chloride and then washed with 1 N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution. The resultant was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (955 mg).

¹H-NMR (CDCl₃) δ: 7.42-7.31 (5H, m), 7.03-7.00 (1H, m), 5.53-5.50 (1H, m), 5.23-5.13 (2H, m), 4.70-4.55 (1H, m), 4.23-4.15 (1H, (n), 4.09-3.94 (1H, m), 3.68-3.59 (1H, m), 3.11-3.03 (1H, m), 1.45-1.42 (12H, m).

LCMS: [M+H]⁺/Rt=367.2/1.77 min^(B)

Reference Example 128-2: N-(tert-butoxycarbonyl)-D-seryl-D-alanine

10% palladium on carbon (48 mg) was added to a methanol (18 mL) solution of the compound of Reference Example 128-1 (955 mg, 2.61 mmol). The reaction mixture was subjected to hydrogen substitution and was stirred for 2 hours at room temperature. After the reaction solution was filtered, the filtrate was concentrated to obtain the title compound (735 mg).

¹H-NMR (CDCl₃) δ: 7.50-7.42 (1H, m), 5.75-5.72 (1H, m), 4.62-4.51 (1H, m), 4.30 (1H, br), 4.03-3.66 (3H, m), 1.47-1.44 (12H, m).

LCMS: [M+H]⁺/Rt=277.1/1.04 min^(B)

Reference Example 128: N²-(tert-butoxycarbonyl)-N-[(2R)-1-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-1-oxopropan-2-yl)-D-serinamide

A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) and the compound of Reference Example 128-2 (86.1 mg, 0.312 mmol) as the starting materials by the same method described in Reference Example 117 to obtain the title compound (203 mg).

¹H-NMR (CDCl₃) δ: 7.24 (1H, d, J=8.1 Hz), 6.92-6.82 (1H, m), 6.41 (1H, d, J=8.1 Hz), 5.46-5.37 (1H, m), 5.02-4.95 (1H, m), 4.72-4.66 (1H, m), 4.51-3.94 (7H, m), 3.65-3.32 (2H, m), 2.65-2.49 (2H, m), 2.36-2.28 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.36-1.23 (9H, m), 1.14-1.01 (3H, m), 0.84 (3H, s).

LCMS: [M+H]⁺/Rt=830.4/2.80 min^(B)

A reaction, work-up, and purification were performed using N^(α)-(tert-butoxycarbonyl)-D-asparagine and tert-butyl N^(α)-(tert-butoxycarbonyl)-D-aspartate as the starting materials by the same method described in Reference Example 128-1 and Reference Example 128-2 to obtain each of Reference Example compounds 129 and 130 shown in Table 2-21.

TABLE 2-21 Reference Example Starting material Structural formula NMR and/or LCMS 129 N^(α)-(tert- butoxycarbonyl)- D-asparagine

LCMS: [M + H]⁺/Rt = 304.1/1.03 min^(B) ¹H-NMR (DMSO-d₆) δ: 12.6 (1H, br), 8.01 (1H, d, J = 8.1 Hz), 7.24 (1H, br), 6.91-6.88 (1H, m), 4.30-4.15 (2H, m), 3.42-3.35 (1H, m), 2.52-2.28 (2H, m), 1.37 (9H, s), 1.26 (3H, d, J = 8.1 Hz). 130 tert-Butyl N^(α)-(tert- butoxycarbonyl)- D-aspartate

LCMS: [M + H]⁺/Rt = 361.2/1.71 min^(B) ¹H-NMR (CDCl₃) δ: 7.19 (1H, d, J = 5.4 Hz), 6.75 (1H, d, J = 8.1 Hz), 4.64-4.46 (2H, m), 2.89-2.57 (2H, m), 1.47-1.45 (21H, m).

A reaction, work-up, and purification were performed using the compound of Reference Example 1-7 and a corresponding commercially available carboxylic acid or the compound of Reference Example 129 as the starting materials by the same method described in Reference Example 42 to obtain each of Reference Example compounds 131 to 134 shown in Table 2-22.

TABLE 2-22 Refe- rence Exam- ple Structural formula NMR and/or LCMS 131

LCMS: [M + H]⁺/Rt = 814.9/2.79 min^(B) ¹H-NMR (CDCl₃) δ: 7.23 (1H, d, J = 8.1 Hz), 6.64- 6.39 (2H, m), 5.50-5.39 (1H, m), 5.01-4.91 (1H, m), 4.63- 4.00 (6H, m), 3.79-3.56 (1H, m), 3.07-2.83 (1H, m), 2.64- 2.58 (2H, m), 2.37-2.26 (1H, m), 2.23-2.13 (1H, m), 2.05- 1.77 (8H, m), 1.59-1.54 (18H, m), 1.44 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.01 (3H, m), 0.84 (3H, s). 132

LCMS: [M + H]⁺/Rt = 786.8/2.77 min^(B) ¹H-NMR (CDCl₃) δ: 7.24- 7.20 (1H, m), 7.00-6.86 (1H, m), 6.41 (1H, d, J = 8.1 Hz), 6.34-6.07 (1H, m), 5.43-5.35 (1H, m), 4.98-4.89 (1H, m), 4.63-4.31 (3H, m), 4.26-4.22 (1H, m), 4.17-4.00 (2H, m), 2.96-2.83 (1H, m), 2.64-2.58 (2H, m), 2.44-2.27 (2H, m), 2.21-2.13 (1H, m), 2.05-2.00 (1H, m, 1.93-1.76 (2H, m), 1.59-1.53 (18H, m), 1.45 (9H, s), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s). 133

LCMS: [M + H]⁺/Rt = 814.8/2.88 min^(B) ¹H-NMR (CDCl₃) δ: 7.24 (1H, d, J = 8.1 Hz), 6.80-6.70 (1H, m), 6.41 (1H, d, J = 8.1 Hz), 5.05-4.90 (2H, m), 4.71- 4.03 (7H, m), 2.65-2.59 (2H, m), 2.37-2.27 (1H, m), 2.22- 2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.76 (2H, m), 1.59- 1.54 (18H, m), 1.45-1.44 (9H, m), 1.36-1.26 (12H, m), 1.14-1.01 (3H, m), 0.84 (3H, s). 134

LCMS: [M + H]⁺/Rt = 857.8/2.71 min^(B) ¹H-NMR (CDCl₃) δ: 7.40- 7.31 (1H, m), 7.23 (1H, d, J = 8.1 Hz), 6.41 (1H, d, J = 8.1 Hz), 6.09-5.95 (1H, m), 5.90-5.79 (1H, m), 5.51-5.41 (1H, m), 5.01-4.92 (1H, m), 4.70-4.00 (7H, m), 2.97-2.88 (1H, m), 2.64-2.48 (3H, m), 2.37-2.27 (1H, m), 2.22-2.13 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.46-1.45 (9H, m), 1.36 (3H, s), 1.32- 1.23 (6H, m), 1.14-1.01 (3H, m), 0.84 (3H, s).

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 and a corresponding commercially available carboxylic acid or the compound of Reference Example 130 as the starting materials by the same method described in Reference Example 3 to obtain each of Reference Example compounds 135 to 137 shown in Table 2-23.

TABLE 2-23 Refe- rence Exam- ple Structural formula NMR and/or LCMS 135

LCMS: [M + H]⁺/Rt = 800.7/2.83 min^(B) ¹H-NMR (CDCl₃) δ: 7.26-7.21 (1H, m), 6.77-6.68 (1H, m), 6.41 (1H, d, J = 8.1 Hz), 5.10-4.92 (2H, m), 4.72- 4.03 (6H, m), 3.85-3.76 (2H, m), 2.65-2.59 (2H, m), 2.36-2.28 (1H, m), 2.22-2.12 (1H, m), 2.04-2.00 (1H, m), 1.93-1.76 (2H, m), 1.56- 1.54 (18H, m), 1.46 (9H, s), 1.36- 1.28 (9H, m), 1.14-1.01 (3H, m), 0.84 (3H, s). 136

LCMS: [M + H]⁺/Rt = 914.7/3.07 min^(B) ¹H-NMR (CDCl₃) δ: 7.24-7.03 (1H, m), 6.42-6.38 (1H, m), 5.66-5.53 (1H, m), 4.99-4.91 (1H, m), 4.69- 4.04 (8H, m), 2.94-2.82 (1H, m), 2.64-2.55 (3H, m), 2.36-2.27 (1H, m), 2.20-2.12 (1H, m), 2.05-2.00 (1H, m), 1.93-1.77 (2H, m), 1.59- 1.53 (18H, m), 1.46-1.43 (18H, m), 1.36 (3H, s), 1.32-1.23 (6H, m), 1.14-1.01 (3H, m), 0.84 (3H, s). 137

LCMS: [M + H]⁺/Rt = 843.6/3.14 min^(B) ¹H-NMR (CDCl₃) δ: 7.22 (1H, d, J = 8.1 Hz), 6.40 (1H, d, J = 8.1 Hz), 5.75-5.67 (1H, m), 4.94-4.89 (1H, m), 4.48-4.32 (3H, m), 4.26-4.22 (1H, m), 4.19-4.11 (1H, m), 4.07- 4.02 (1H, m), 2.86-2.71 (1H, m), 2.64-2.48 (3H, m), 2.37-2.26 (1H, m), 2.23-2.13 (1H, m), 2.05-2.00 (1H, m), 1.92-1.77 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.46-1.43 (18H, m), 1.36 (3H, s), 1.28 (3H, s), 1.14-1.00 (3H, m), 0.83 (3H, s).

Reference Example 138: tert-butyl 4-[2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy)azetidin-1-yl}-1-(methylamino)-2-oxoethyl]-1H-imidazole-1-carboxylate

Reference Example 138-1: {[(benzyloxy)cabonyl]amino}(1H-imidazol-4-yl)acetic acid

Sodium hydrogen carbonate (5.78 g, 68.8 mmol) and benzyl chloroformate (5.87 g, 34.4 mmol) were added to an ethanol/water (1:1) mixture solution (57 mL) of the compound of Reference Example 36-2 (3.68 g, 17.2 mmol) while cooling with ice. After stirring for 15 minutes, the reaction solution was warmed up to room temperature, and stirred for another 12 hours. Saturated ammonium chloride water was added to the reaction solution, which was extracted with ethanol (40 mL) and dichloromethane (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by chromatography (dichloromethane/methanol-10/1) to obtain the title compound (1.7 g).

¹H-NMR (500 MHz, CDCl₃) δ: 8.86-8.82 (1H, m), 7.51-7.47 (1H, m), 7.37-7.24 (5H, m), 5.57 (1H, s), 5.10 (2H, s).

Reference Example 138-2: tert-butyl 6-({1-[{[(benzyloxy)carbonyl]amino}(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Triethylamine (5 mL, 18 mmol), ethylcarbodiimide (1.16 g, 6 mmol), and 1-hydroxybenzotriazole (1.64 g, 12 mmol) were added to a DMF (24 mL) solution of the compound of Reference Example 138-1 (1.7 g, 6.1 mmol) and the compound of Reference Example 1-8 (1.7 g, 3.0 mmol), and the reaction mixture was stirred for 12 hours at room temperature. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution, which was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated saline (30 mL), then dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (dichloromethane/methanol=50/1) to obtain the title compound (956 mg).

¹H-NMR (500 MHz, CDCl₃) δ: 9.30 (1H, brs), 7.59 (1H, s), 7.40-7.22 (5H, m), 7.21-7.05 (2H, m), 6.03 (1H, brs), 5.48-5.32 (2H, m), 5.15-5.08 (4H, m), 4.43-4.06 (2H, m), 3.79-3.67 (3H, m), 2.63-1.79 (3H, m), 1.54 (9H, s), 1.53 (9H, s), 1.36-1.16 (6H, m), 1.13-1.01 (2H, m), 0.89-0.80 (4H, m).

Reference Example 138-3: tert-butyl 4-(1-{[(benzyloxy)carbonyl]amino}-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-imidazole-1-carboxylate

Triethylamine (0.641 mL, 4.6 mmol) and di-tert-butyl dicarbonate (503 mg, 2.3 mmol) were added to a dichloromethane (5.75 mL) solution of the compound of Reference Example 138-2 (956 mg, 1.15 mmol), and the reaction mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, which was extracted with dichloromethane (10 mL). The organic phase was dried over sodium sulfate, then filtered and concentrated. The resulting residue was purified by column chromatography (dichloromethane/methanol-50/1) to obtain the title compound (228 mg).

¹H-NMR (500 MHz, CDCl₃) δ: 8.02-7.98 (1H, m), 7.38-7.12 (7H, m), 6.39-6.07 (1H, m), 5.32-4.05 (5H, m), 3.50-3.49 (1H, m), 2.63-1.78 (7H, m), 1.62 (9H, s), 1.56 (9H, s), 1.52 (9H, s), 1.38-1.23 (8H, m), 1.15-1.08 (2H, m), 1.05-0.83 (5H, m).

Reference Example 138-4: tert-butyl 4-(1-amino-2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-2-oxoethyl)-1H-imidazole-1-carboxylate

Palladium hydroxide (22 mg) was added to a methanol solution (4 mL) of the compound of Reference Example 138-3 (228 mg, 0.245 mmol), and the reaction mixture was stirred under a hydrogen atmosphere at room temperature. After 12 hours, the reaction solution was filtered through celite, and the filtrate was concentrated. The resulting residue was purified by column chromatography (dichloromethane/methanol 50/1) to obtain the title compound (123 mg).

¹H-NMR (500 MHz, CDCl₃) δ: 8.02-8.00 (1H, m), 7.35-7.20 (2H, m), 6.40-6.37 (1H, m), 4.96-4.90 (1H, brs), 4.45-4.39 (m, 1H), 4.25-4.20 (1H, m), 4.13-4.11 (1H, m), 2.63-2.60 (2H, m), 2.35-2.28 (1H, m), 2.17-2.14 (1H, m), 2.03-2.01 (1H, m), 1.61 (9H, s), 1.56 (9H, s), 1.52 (9H, s), 1.28-1.26 (6H, m), 1.13-1.10 (1H, m), 0.83 (6H, s).

Reference Example 138: tert-butyl 4-[2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-1-(methylamino)-2-oxoethyl]-1H-imidazole-1-carboxylate

A formalin solution (30% methanol solution, 2.32 μL, 0.231 mmol) was added to a diethyl ether solution (3 mL) of the compound of Reference Example 138-4 (123 mg, 0.154 mmol), and the reaction mixture was stirred for 1.5 hours at room temperature. Dichloromethane (10 mL) was added to the reaction solution. The organic layer was washed three times with water (10 mL), dried over sodium sulfate, then filtered and concentrated. Sodium triacetoxyborohydride (65 mg, 0.308 mmol) was added to a dichloromethane/acetic acid (1:1) mixture solution (3 mL) of the resulting residue, and the reaction mixture was stirred for 1.5 hours at room temperature. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with dichloromethane (10 mL). The retrieved organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by preparative thin-layer chromatography (dichloromethane/methanol=10/1) to obtain the compound of Reference Example 138 (26 mg) and the compound of Reference Example 139 (42 mg).

¹H-NMR (500 MHz, CDCl₃) δ: 8.00 (1H, d, J=6.3 Hz), 7.35 (1H, d, J=8.6 Hz), 7.24-7.15 (1H, m), 6.38 (1H, dd, J=8.6, 8.3 Hz), 4.95-4.72 (1H, m), 4.66-4.05 (4H, m), 2.63-2.58 (2H, m), 2.41 (3H, s), 2.35-1.78 (5H, m), 1.47 (9H, s), 1.52 (9H, s), 1.52 (9H, s), 1.35 (3H, s), 1.28 (3H, s), 1.28-1.23 (2H, m), 1.24-1.08 (2H, m), 1.04-1.02 (1H, m), 0.83 (3H, s).

Reference Example 139: tert-butyl 4-[2-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-1-(dimethylamino)-2-oxoethyl]-1H-imidazole-1-carboxylate

¹H-NMR (500 MHz, CDCl₃) δ: 8.04-8.03 (1H, m), 7.52-7.49 (1H, m), 7.21-7.19 (1H, m), 6.39-6.37 (1H, m), 4.91-3.98 (6H, m), 2.63-2.58 (2H, m), 2.35-1.78 (11H, m), 1.56 (9H, s), 1.53 (9H, s), 1.52 (9H, s), 1.35-1.23 (5H, m), 1.14-1.03 (3H, m), 0.83 (4H, s).

A reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 3 to obtain each of Reference Example compounds 140 to 147 shown in Tables 2-24 and 2-25. Further, a reaction, work-up, and purification were performed using the compound of Reference Example 1-8 as the starting material by the same method described in Reference Example 36-4 to obtain Reference Example compounds 148 and 149 shown in Table 2-26.

TABLE 2-24 Reference Example Structural formula NMR and/or LCMS 140

LCMS: [M + H]⁺/Rt = 773.00/1.394 min^(A1) H-NMR (CD₃OD) δ: 7.39-7.26 (6H, m), 6.67 (1H, d, J = 8.5 Hz), 5.12-5.05 (3H, m), 4.39-4.33 (1H, m), 4.29 (2H, d, J = 8.5 Hz), 4.00-3.94 (1H, m), 3.74-3.67 (2H, m), 3.34 (2H, s), 2.58 (2H, t, J = 7.9 Hz), 2.39-2.32 (1H, m), 2.21-2.16 (1H, m), 1.99 (1H, t, J = 5.5 Hz), 1.89-1.87 (1H, m), 1.79 (1H, d, J = 15.3 Hz), 1.55 (9H, d, J = 7.9 Hz), 1.52 (9H, s), 1.35 (3H, s), 1.29 (3H, s), 1.08 (2H, t, J = 8.2 Hz), 0.99 (1H, d, J = 10.4 Hz), 0.86 (3H, s). 141

LCMS: [M + H]⁺/Rt = 773/2.275 min^(H)

TABLE 2-25 142

LCMS: [M + H]⁺/Rt = 905/2.433 min^(H) 143

LCMS: [M + H]⁺/Rt = 812/2.217 min^(H) 144

LCMS: [M + H]⁺/Rt = 877/2.150 min^(H) 145

LCMS: [M + H]⁺/Rt = 892/1.411 min^(E) 146

LCMS: [M + H]⁺/Rt = 857.7/3.17 min^(B) 147

LCMS: [M + H]⁺/Rt = 800.7/2.81 min^(B)

TABLE 2-26 148

LCMS: [M + H]⁺/Rt = 773.54/3.960 min^(I) 149

LCMS: [M + H]⁺/Rt = 773.54/3.940 min^(I)

Reference Example 150: (4S)-4-[(tert-butoxycarbonyl)amino]-6-{3-[2-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl)oxy]-4-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}phenoxy]azetidin-1-yl}-6-oxohexanoic acid

10% palladium on carbon (113 mg) was added to a methanol (7 mL) solution of the compound of Reference Example 142 (334 mg, 0.369 mmol). The reaction mixture was subjected to hydrogen substitution and was stirred for 2 hours at room temperature. After filtering the reaction solution, the filtrate was concentrated to obtain the title compound (329 mg).

LCMS: [M+H]⁺/Rt=815.5/2.211 min^(H)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 144 and 145 as the starting materials by the same method described in Reference Example 151 to obtain Reference Example compounds 151 and 152 shown in Table 2-27, respectively.

TABLE 2-27 Reference Starting Example material Structural formula NMR and/or LCMS 151 Reference Example 144

LCMS: [M + H]⁺/Rt = 787/2.247 min^(H) 152 Reference Example 145

LCMS: [M + H]⁺/Rt = 801/2.231 min^(H)

Reference Example 153: tert-butyl 6-[(1-{(3S)-6-amino-3-[(tert-butoxycarbonyl)amino]-6-oxohexanoyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

N,N-diisopropylethylamine (0.131 mL, 0.750 mmol) and HATU (107 mg, 0.281 mmol) were added to a DMF (1 mL) solution of the compound of Reference Example 150 (153 mg, 0.188 mmol), and the reaction mixture was stirred for 30 minutes at room temperature. Ammonium chloride (16.1 mg, 0,300 mmol) was added, and the reaction mixture was stirred for 2 hours at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and then saturated saline, dried over sodium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (45.7 mg).

LCMS: [M+H]⁺/Rt=814.5/2.204 min^(H)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 151 and 152 as the starting materials by the same method described in Reference Example 153 to obtain Reference Example compounds 154 and 155 shown in Table 2-28, respectively.

Example 1: 7-[(1-acetylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

The compound of Reference Example 1 (105 mug) and phenylboronic acid (19 mg) were added to CPME (0.9 mL). 3 mol/L hydrochloric acid (1.14 mL) was added thereto, and the reaction mixture was stirred overnight at room temperature. The aqueous layer was concentrated and purified by reversed phase column chromatography (eluent: acetonitrile/water 1/99 to 95/5) to obtain the title compound (9.2 mag).

¹H-NMR (CD₃OD) 5: 7.16-7.08 (1H, m), 6.35-6.25 (1H, m), 5.06-4.97 (1H, m), 4.58-4.52 (1H, m), 4.37-4.30 (1H, m), 4.22-4.17 (1H, m), 3.96-3.89 (1H, m), 2.70-2.62 (2H, m), 1.86 (3H, s), 1.05-1.01 (2H, m).

Example 2: 2-hydroxy-7-({1-[(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

Triethylsilane (0.2 mL) and, additionally, TFA (0.9 mL) was added to the compound of Reference Example 3 (96 mg) and phenylboronic acid (14 mg), and the reaction mixture was stirred for 3 hours at room temperature. After concentrating the reaction mixture, the residue was washed with a mixture solvent of diethyl ether/hexane (1:1). The resulting solid was dissolved in methanol and purified by reversed phase chromatography and concentrated. After adding 0.2 mL of aqueous 1 N hydrochloric acid solution to the residue, the mixture was concentrated to obtain the compound of interest (21.6 mg).

LCMS: [M+H]⁺/Rt=372/0.44 min^(C)

Example 3: 2-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

Triethylsilane (0.2 mL) and, additionally, TFA (0.9 mL) was added to the compound of Reference Example 2 (96 mg) and phenylboronic acid (14 mg), and the reaction mixture was stirred for 3 hours at room temperature. After concentrating the reaction mixture, the residue was washed with a mixture solvent of diethyl ether/hexane (1:1). The resulting solid was dissolved in methanol and purified by reversed phase chromatography and concentrated to obtain the compound of interest (28 mg).

¹H-NMR (CD₃OD) δ: 7.16-7.00 (1H, m), 6.37-6.20 (1H, m), 5.06-4.97 (1H, m), 4.31-4.25 (2H, m), 3.98-3.94 (2H, m), 2.96 (3H, s), 2.68-2.65 (2H, m), 1.05-1.01 (2H, m)

Example 4: 8-({1-[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

The compound of Reference Example 17 (119 mg), phenylboronic acid (16.2 mg), acetonitrile (2.0 mL), hexane (2.0 mL), and 4 N hydrochloric acid/dioxane solution (1.0 mL) were added, and the reaction mixture was stirred for 19 hours at room temperature. After allowing it to stand, the supernatant (top layer) of the reaction solution separated into two layers was removed, and the remaining bottom layer was washed 5 times with hexane and twice with diethyl ether (the washing process removes the supernatant after standing). The solid produced in the solution at the bottom layer was washed with acetonitrile (5.0 mL). The residue of the solid obtained by removing the solvent was dried under reduced pressure. The resulting dried residue was dissolved in water. An aqueous 2 N sodium hydroxide solution (0.5 mL) was added. The mixture was purified by reversed phase column chromatography to obtain the title compound (41.7 mg) as a colorless solid.

¹H-NMR (D₂O) 5: 7.20-7.13 (2H, m), 6.83-6.75 (3H, m), 5.98-5.90 (1H, m), 5.00-4.91 (1H, m), 4.63-3.90 (5H, m), 2.59-2.50 (2H, m), 0.39-0.29 (2H, m).

A reaction, work-up, and purification were performed using Reference Example compounds 4 to 16 and 18 to 33 shown in Table 2 as the starting materials by the same method described in Example 4 to obtain each of Example compounds to 33. However, if a free form is the final product (Examples 5 and 34), the free form was obtained without sodium hydroxide treatment. If a hydrochloride (hydrochloride salt) is the final product (Example 6), the hydrochloride was obtained by purifying the compound by using reversed phase chromatography and then adding hydrochloric acid and concentrating. A reaction, work-up, and purification were performed using Reference Example compound 34 as the starting material by the same method described in Example 3 to obtain Example compound 34.

TABLE 3 Starting Example material Structural formula NMR and/or LCMS  5 Reference Example 4

LCMS: [M +H]⁺/Rt = 447/0.626min^(C)  6 Reference Example 5

¹H-NMR (CD₃OD) δ: 8.67-8.64 (1H, m), 8.06-8.01 (2H, m), 7.59-7.56 (1H, m), 7.18-7.15 (1H, m), 6.38-6.35 (1H, m), 5.13-5.10 (2H, m), 4.72-4.69 (1H, m), 4.63-4.60 (1H, m), 4.22-4.19 (1H, m), 2.70 (2H, t, J = 7.3 Hz), 1.05 (2H, t, J = 7.3 Hz).  7 Reference Example 6

¹H-NMR(D₂O) as a mixture of keto and enol forms δ: 6.87-6.82 (1H, m), 6.04-6.02 (1H, m), 5.02-4.97 (1H, m). 4.65-3.64 (4H, m), 3.20-3.13 (2H, m), 2.57-2.54 (2H, m), 2.11 and 2.07 (3H, s) and 0.36-0.33 (2H, m).  8 Reference Example 7

¹H-NMR(D₂O) δ: 8.32-8.31 (1H, m), 6.94-6.92 (1H, m), 6-94-6.92 (1H, m), 5.13-5.11 (1H, m), 4.99-4.94 (1H, m), 4.65-4.59 (2H, m), 4.28-4.25 (1H, m), 2.63-2.60 (2H, m), and 0.45-0.42 (2H, m).  9 Reference Example 8

¹H-NMR (D₂O) δ: 8.41 (1H, d, J = 6.4 Hz), 7.83 (1H, t, J = 7.8 Hz), 7.76 (1H, dd J = 7.8, 1.8 Hz), 7.73-7.69 (1H, m), 6.91 (1H, d, 3= 7.8 Hz), 6.07 (1H, d, J = 7.8 Hz), 5.15-5.10 (1H, m), 4.69-4.63 (1H, m), 4.47 (1H, dd, 3 = 9.6, 7.3 Hz), 4.32 (1H, dd, J = 13.3, 4.1 Hz), 4.20 (1H, dd, J = 9.6, 3.2 H2), 2.61 (2H, t, J = 7.1 H2), 0.44 (2H, s). 10 Reference Example 9

¹H-NMR (D₂O) as a mixture of isomers δ: 7.46-7:38 (5H, m), 6.89-6.80 (1H, m), 6.01-5.91. (1H, m), 5.04-4.93 (0.5H, m), 4.71-4.59 (1.5H, m), 4.49- 4.38 (0.5H, m), 4.22-4.07 (1H, m), 4.01-3.91 (1H, m), 2.63-2.50 (2H, m), 0.45-0.30 (2H, m). 11 Reference Example 10

¹H-NMR (D₂O) δ: 7.65-7.49 (5H, m), 6.88 (1H, d, J = 8.2 Hz), 6.04 (1H, d, J = 8.2 Hz), 5.04 (1H, td, J = 7.0, 3.7 Hz), 4.65 (1H, dd, J = 10.1, 6.4 Hz), 4.57 (1H, dd, J = 11.4, 6.9 Hz), 4.45 (1H, dd, J = 10.5, 2.7 Hz), 4.23 (1H, dd, J = 10.8, 3.4 Hz), 2.58 (2H, t, J = 6.9 Hz), 0.38 (2H, t, J = 7.1 Hz). 12 Reference Example 11

¹H-NMR (D₂O) δ: 8.72 (1H, d, J = 1.4 Hz), 8.63 (1H, dd, J = 5.0, 1.4 Hz), 8.05 (1H, dt, J = 7.8, 1.8 Hz), 7.53 (1H, dd, J = 7.8, 5.0 Hz), 6.85 (1H, d, J = 8.2 Hz), 6.01 (1H, d, J = 8.2 Hz), 5.04 (1H, td, J = 7.9, 4.7 Hz), 4.66 (1H, t, J = 8.5 Hz), 4.56 (1H, dd, J = 11.2, 6.6 Hz), 4.44 (1H, dd, J = 10.1, 3.7 Hz), 4.23 (1H, dd, J = 11.2, 3.9 Hz), 2.55 (2H, t, J = 7.1 Hz), 0.34 (2H, t, J = 6.9 Hz). 13 Reference Example 12

¹H-NMR (CD₃OD) δ: 8.85-8.78 (1H, m), 8.62-8.52 (1H, m), 8.06-7.95 (2H, m), 7.18 (1H, d, J = 8.2 Hz), 6.36 (1H, d, J = 7.9 Hz), 5.19-5.06 (1H, m), 4.83-4.70 (2H, m), 4.49-4.38 (2H, m), 4.14-4.02 (2H, m), 2.71 (2H, t, J = 7.7 Hz), 1.07 (2H, t, J = 7.7 Hz). 14 Reference Example 13

¹H-NMR (CD₃OD)) δ: 8.87-8.74 (2H, m), 8.62-8.53 (1H, m), 8.12-8.03 (1H, m), 7.18 (1H, d, J = 8.2 Hz), 6.36 (1H, d, J = 8.2 Hz), 5.18-5.09 (1H,m), 4.82-4.70 (2H, m), 4.49- 4.36 (2H, m), 4.07-3.99 (2H, m), 2.71 (2H, t, J = 7.7 Hz), 1.07 (2H, t, J = 7.7 Hz). 15 Reference Example 14

¹H-NMR (D₂O) as a mixture of isomers δ: 7.43-7.29 (5H, m), 6.84-6.76 (1H, m), 6.01-5.89 (1H, m), 4.95-4.83 (1H, m), 4.65-4.53 (1H, m), 4.41-3.50 (4H, m) 2.52 (2H, t, J = 6.6 Hz), 0.31 (2H, q, J = 6.4 Hz). 16 Reference Example 15

¹H-NMR (D₂O) δ: 8.32 (2H, d, J = 6.0 Hz), 7.19 (2H, d, J = 6.0 Hz), 6.74 (1H, d, J = 8.2 Hz), 5.91 (1H, d, J = 8.2 Hz), 4.91-4.80 (1H,m), 4.52-4.49 (1H, m), 4.29-4.20 (2H, m), 3.96-3.91 (1H, m), 3.52 (2H, s), 2.44 (2H, t, J = 7.1 Hz), 0.23 (2H, t, J = 7.1 Hz). 17 Reference Example 16

¹H-NMR (D₂O) δ: 7.03 (2H, d, J = 8.2 Hz), 6.86 (1H, d, J = 8.2 Hz), 6.67 (2H, d, J = 8.2 Hz), 6.01 (1H, d, J = 8.2 Hz), 4.99-4.93 (1H, m), 4.62-4.55 (1H, m), 4.29-4.38 (2H, m), 4.05-3.99 (1H, m), 3.46-3.36 (2H, m), 2.56 (2H, t, J = 7.1 Hz), 0.35 (2H, t, J = 7.1 Hz). 18 Reference Example 18

¹H-NMR (D₂O) δ: 8.51 (1H, s), 8.12 (1H, s), 6.94 (1H, d, J = 8.2 Hz), 6.11 (1H, d, J = 8.2 Hz), 5.20-5.05 (3H, m), 4.72-4..64 (1H, m), 4.52-4.45 (1H, m), 4.42-4.37 (1H, m), 4.20-4.13 (1H, m), 2.62 (2H, t, J = 6.9 Hz), 0.46 (2H, t, J = 6.9 Hz). 19 Reference Example 19

¹H-NMR (D₂O)) δ: 7.75-7.65 (1H, m), 7.42-7.35 and 7.70-7.09 (1H, m), 6.90- 6.82 (1H, m), 6.02-5.96 (1H, m), 5.05- 4.85 and 4.70-3.91 (6H, m), 2.62-2.50 (2H, m), 0.43-0.31 (2H, m). 20 Reference Example 20

¹H-NMR (D₂O)) δ: 7.41-7.24 (5H, m), 6.36 (1H, d, J = 8.2 Hz), 6.02 (1H, d, J = 8.2 Hz), 5.01-4.96 (1H, m), 4.63-4.58 (1H, m), 4.40-4.32 (2H, m), 4.08-4.01 (1H, m), 3.58 (2H, s), 2.56 (2H, t, J = 7.1 Hz), 0.35 (2H, t, J = 6.9 Hz). 21 Reference Example 21

¹H-NMR (D₂O) δ: 7.39-7.28 (2H, m), 7.30-7.22 (3H, m), 6.84 (1H, d, J = 7.8 Hz), 5.92 (1H, d, J = 7.8 Hz), 4.28-4.20 (1H, m), 4.17-4.09 (1H, m), 3.98-3.88 (2H, m), 2.94-2.80 (2H, m), 2.60-2.50 (2H, m), 2.50-2.43 (2H, m), 0.40-0.31 (2H, m). 22 Reference Example 22

¹H-NMR (D₂O) δ: 7.80-7.62 (1H, m), 7.22-7.0 (2H, m), 6.96-6.85 (1H, m), 6.13-5.99 (1H, m), 5.10-5.05 (1H, m), 4.64-4.53 (1H, m), 4.47-4.38 (1H, m), 4.36-4.27 (1H, m), 4.20-4.05 (1H, m), 2.67 (2H, m), 0.50-0.38 (2H,m). 23 Reference Example 23

¹H-NMR (CD₃OD) δ: 9.18 (1H, s), 7.21- 7.14 (1H, m), 6.44-6.12 (1H, m), 5.38 (2H, s), 5.22-5.08 (1H, m), 4.80-4.69 (1H, m), 4.51-4.38 (2H, m), 4.15-4.03 (1H, m), 2.78-2.65 (2H, m), 1.14-0.98 (2H, m). 24 Reference Example 24

¹H-NMR (D₂O) δ: 6.89 (1H, d, J = 8.2 Hz), 6.05 (1H, d, J = 8.2 Hz), 5.03-4.97 (1H, m), 4.54 (1H, dd, J = 9.6, 6.9 Hz), 4.40 (1H, dd, J = 11.0, 6.9 Hz), 4.29 (1H, dd, J = 9.6, 3.7 Hz), 4.08 (1H, dd, J = 11.0, 3.7 Hz), 3.85 (1H, d, J = 16.3 Hz), 3.75 (1H, d, J= 16.3 Hz), 2.58 (2H, t, J = 6.9 Hz), 0.41 (2H, t, J = 7.1 Hz). 25 Reference Example 25

¹H-NMR (D₂O) δ: 7.41-7.21 (5H, m), 6.97-6.78 (1H, m), 5.93-5.80 (1H, m), 4.59-4.52, 4.33-4.25, 4.33-4.25, 4.18- 4.10, 4.05-3.99, 3.91-3.82, 3.74-3.65, 3.53-3.48, 3.38-3.30 (6H, m), 2.99-2.90 (1H, m), 2.88-2.72 (1H, m), 2.60-2.50 (2H, m), 0.43-0.27 (2H, m). 26 Reference Example 26

¹H-NMR (D₂O) δ: 7.14-7.01 (2H, m), 6.88-6.76 (3H, m), 5.86-5.70 (1H, m), 4.61-4.56, 4.30-4.12, 4.00-3.82, 3.63- 3.44, 2.95-2.80, 2.72-2.48 (10H, m), 0.44-0.26 (2H, m). 27 Reference Example 27

¹H-NMR (D₂O) δ: 7.69, 7.52 (1H, s), 6.93-6.83 (2H, m), 5.99-5.78 (1H, m), 4.42-4.07, 4.01-3.79, 3.70-3.50, 3.05- 2.91 (5H, m), 2.91-2.66 (1H, m), 2.61- 2.48 (2H, m), 0.42-0.28 (2H, m). 28 Reference Example 28

¹H-NMR (D₂O) δ: 6.87 (1H, d, J = 8.2. Hz), 6.03 (1H, d, J = 8.2 Hz), 5.04-4.96 (1H, m), 4.68-4.58 (1H, m), 4.43-4.28 (2H, m), 4.08-4.00 (1H, m), 3.19-3.13 (1H, m), 2.56 (2H, t, J = 6.9 Hz), 1.81- 1.73 (1H, m), 1.00-0.81 (6H, m), 0.35 (2H, t, J = 7.1 Hz). 29 Reference Example 29

¹H-NMR (D₂O) δ: 7.73, 7.54 (1H, s), 6.98-6.80 (2H, m), 5.96-5.80 (1H, m), 4.42-4.11, 4.04-3.83, 3.74-3.66, 3.65- 3.57, 3.08-2.96 (5H, m), 2.90-2.74 (2H, m), 2.64-2.50 (2H, m), 0.48-0.31 (2H, m). 30 Reference Example 30

¹H-NMR (D₂O) δ: 7.50-7.31 (5H, m), 6.89-6.84 (1H, m), 6.03-5.95 (1H, m), 5.33-5.27 (1H, m), 5.15-4.97 (1H, m), 4.50-4.28 (2H, m), 4.20-3.95 (2H, m), 3.33 (6H, dt, J = 28.1, 9.6 Hz), 2.63- 2.48 (2H, m), 1.16-1.02 (3H, m), 0.50- 0.30 (2H, m). 31 Reference Example 31

¹H-NMR (D₂O) δ: 6.87 (1H, d, J = 7.9 Hz), 6.04 (1H, d, J = 7.9 Hz), 5.09-4.96 (1H, m), 4.90-4.84 (1H, m), 4.66-4.52 (1H, m), 4.43-4.30 (2H, m), 4.10-4.00 (1H, m), 3.93-3.80 (1H, m), 3.08-2.90 (2H, m), 2.57 (2H, t, J = 6.9 Hz), 2.28- 2.02 (1H, m), 1.93-1.68 (3H, m), 0.36 (2H, t, J = 6.9 Hz). 32 Reference Example 32

LCMS: [M + H]⁺/Rt = 361/0.87min^(B) 33 Reference Example 33

¹H-NMR (D₂O) δ: 7.56 (1H, s), 6.93 (1H, s), 6.83 (1H, d, J = 8.2 Hz), 5.99 (1H, d, J = 8.2 Hz), 5.04-4.93 (1H, m), 4.57-4.48 (1H, m), 4.42-4.33 (1H, m), 4.23-4.17 (1H, m), 4.09-3.98 (1H, m), 3.14 (2H, t, J = 6.6 Hz), 2.82 (2H, t, J = 6.6 Hz), 2.52 (2H, t, J = 6.9 Hz), 0.31 (2H, t, J = 6.9 Hz) 34 Reference Example 34

¹H-NMR (CD₃OD) δ: 6.96 (1H, d, J = 7.9. Hz), 6.90-6.87 (1H, m), 6.80-6.78 (2H, m), 6.58 (1H, d, J = 7.9 Hz), 4.99-4.97 (2H, m), 4.68-4.65 (1H, m), 4.48-4.45 (1H, m), 4.18-4.16 (1H, m), 2.57 (2H, t, J = 7.3 Hz), 0.51 (2H, t, J = 7.3 Hz).

The names of the compounds of Examples 5 to 34 are described below.

-   7-({1-[(2-amino-1,3-thiazol-4-yl)(methoxyimino)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 5) -   2-hydroxy-7-{[1-(pyridine-2-carbonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 6) -   4,4-dihydroxy-8-({1-[(methylsulfanyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 7) -   4,4-dihydroxy-8-{[1-(1H-1,2,4-triazole-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 8) -   4,4-dihydroxy-8-{[1-(1-oxido-2-pyridinylcarbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 9) -   8-({1-[(2R)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 10) -   8-[(1-benzoylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 11) -   4,4-dihydroxy-8-{[1-(pyridine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 12) -   4,4-dihydroxy-8-({1-[(pyridin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 13) -   4,4-dihydroxy-8-({1-[(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 14) -   8-({1-[(2S)-2-amino-2-phenylacetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 15) -   4,4-dihydroxy-8-({1-[(pyridin-4-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 16) -   4,4-dihydroxy-8-({1-[(4-hydroxyphenyl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 17) -   4,4-dihydroxy-8-({1-[(1H-1,2,4-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 18) -   8-({1-[amino(1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 19) -   4,4-dihydroxy-8-{[1-(phenylacetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 20) -   4,4-dihydroxy-8-{[1-(3-phenylpropanoyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 21) -   4,4-dihydroxy-8-({1-[(1H-imidazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 22) -   4,4-dihydroxy-8-({1-[(1H-tetrazol-1-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 23) -   4,4-dihydroxy-8-({1-[(2H-tetrazol-5-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 24) -   4,4-dihydroxy-8-[(1-D-phenylalanylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 25) -   4,4-dihydroxy-8-[(1-D-tyrosylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 26) -   8-[(1-D-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 27) -   4,4-dihydroxy-8-[(1-D-valylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 28) -   8-[(1-L-histidylazetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 29) -   8-[(1-{(2R)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 30) -   4,4-dihydroxy-8-[(1-D-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 31) -   4,4-dihydroxy-8-[(1-L-prolylazetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 32) -   8-[(1-{[4-(2-aminoethyl)-1H-imidazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 33) -   7-{[1-(3,4-dihydroxybenzoyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 34)

Example 35: 2-hydroxy-7-{[1-(hydroxycarbamoyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

Phenylboronic acid (10.3 mg), 4 N hydrocholic acid/ethyl acetate solution, and hexane (3.6 mL) were added to an acetonitrile (0.73 mL) solution of the compound of Reference Example 35. The reaction mixture was stirred for 7 hours at room temperature and allowed to stand overnight. The acetonitrile phase was washed with hexane and concentrated. The residue was washed with acetonitrile to obtain the title compound (0.4 mg).

LCMS: [M+H]⁺/Rt=323/0.489 min^(C)

Example 36: 7-({1-[(2R)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

Phenylboronic acid (0.146 g) and 1 N hydrochloric acid/acetic acid solution (25.2 mL) were added to Reference Example (R)-36 (1.0 g). The reaction mixture was stirred for 1 hour at room temperature and then concentrated. The residue was dissolved in methanol (3 mL) and washed twice with heptane (6 mL)(the washing process removes the supernatant (top layer) after standing). The bottom layer was concentrated under reduced pressure, and the resulting residue was purified by reversed phase column chromatography to obtain the title compound (200 mg).

¹H-NMR (600 MHz, D₂O) δ: 7.56 (1H, m), 6.99 (1H, m), 6.73 (1H, d, J=8.4 Hz), 5.86 (1H, d, J=8.4 Hz), 4.86-4.65 (2H, m), 4.51-4.46 (0.5H, m), 4.30-4.14 (2H, m), 3.96-3.82 (1.5H, m), 2.45-2.43 (2H, m), 0.24-0.21 (2H, m).

LCMS: [M+H]⁺/Rt=387.05/0.421 min^(C)

Example 37: 8-({1-[(2S)-2-amino-2-(1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

Phenylboronic acid (2.46 mg), hexane (0.337 mL), and 4 N hydrochloric acid/cyclopentyl methyl ether solution (0.151 mL) were added to an acetonitrile (0.337 mL) solution of the compound of Reference Example (S)-36 (18.1 mg), and the reaction mixture was stirred for 16 hours at room temperature. After allowing it to stand, the supernatant (top layer) of the reaction solution separated into two layers was removed, and the remaining bottom layer was washed with hexane (the washing process removes the supernatant after standing). The solid produced in the solution at the bottom layer was washed with diethyl ether. The residue of the solid obtained by removing the solvent was dried under reduced pressure. The resulting dried residue was dissolved in water. An aqueous 2 N sodium hydroxide solution (0.1 mL) was added. The mixture was purified by reversed phase column chromatography to obtain the title compound (7.8 mg) as a white solid.

LCMS: [M+H]⁺/Rt=387.00/0.428 min^(C)

The column retention times of the compound of Example 36 and the compound of Example 37 in chiral chromatography were the following.

Column: CROWNPAK CR-I(−)(0.30 cm I.D.×15 cm L)(Daicel Corporation)

Mobile phase: aqueous perchloric acid solution (pH 1.0)/acetonitrile (60% perchloric acid: 1.7%)

Flow rate: 0.5 mL/min

Temperature: 25° C.

Rt of compound of Example 36: 6.001 min

Rt of compound of Example 37: 3.968 min

Optical purity of Example 36 (computed by HPLC area percentage value): 98.5% ee

Optical purity of Example 37 (computed by HPLC area percentage value): 98.3% ee

The stereostructure of the compound of Example 36 was estimated to be an R form by Mosher's method (reference document for Mosher's method include: The Journal of Organic Chemistry, 2016, 81, 7373).

Example 38: 8-({1-[amino(1-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic acid disodium salt

Phenylboronic acid (18.6 mg) and 4 N hydrochloric acid/cyclopentyl methyl ether solution (1.21 mL) were added to an acetic acid (1.61 mL) solution of the compound of Reference Example 37 (130 mg) while cooling with ice, and the reaction mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure. The resulting dried residue was dissolved in water. An aqueous 2 N sodium hydroxide solution (0.402 mL) was added, and the mixture was purified by reversed phase column chromatography to obtain the title compound (5 mg) as a white solid.

LCMS: [M+H]⁺/Rt=401.31/0.473 min^(C)

Example 39: 2-hydroxy-7-{[1-(4H-1,2,4-triazole-3-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid trifluoroacetate

Phenylboronic acid (35.6 mg), hexane (2.9 mL), and TFA (2.23 mL) were added to an acetonitrile (2.9 mL) solution of the compound of Reference Example 41 (205 mg), and the reaction mixture was stirred for 5 hours at room temperature. After allowing it to stand, the supernatant (top layer) of the reaction solution separated into two layers was removed, and the remaining bottom layer was washed with hexane (the washing process removes the supernatant after standing). The solid produced in the solution at the bottom layer was washed with diethyl ether. The residue of the solid obtained by removing the solvent was dried under reduced pressure. The resulting dried residue was purified by reversed phase column chromatography to obtain the title compound (39.8 mg) as a colorless solid.

¹H-NMR (CD₃OD) δ: 8.69 (1H, s), 7.11 (1H, d, J=8.1 Hz), 6.21 (1H, d, J=8.1 Hz), 4.95-4.85 (1H, m), 4.44-4.35 (2H, m), 4.04-3.99 (2H, m), 2.65 (2H, t, J=8.1 Hz), 1.04 (2H, t, J=8.1 Hz).

LCMS: [M+H]⁺/Rt=395.1/1.24 min^(B)

Example 40: 7-({1-[2-amino-2-(1H-imidazol-4-yl)(2H) ethanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid dihydrochloride

Acetic acid-d1 (3 mL) was added to the compound of Reference Example 36-4 (0.3 g, 0.377 mmol), and the reaction mixture was stirred for 4 days at room temperature. Phenylboronic acid (46 mg, 0.377 mmol) and 4 N hydrochloric acid cyclopentyl methyl ether solution (2 mL, 8.0 mmol) were then added, and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was dried and solidified under reduced pressure. The resulting dried residue was dissolved in methanol (1 mL), and isopropanol (10 mL) was added. The precipitated solid was filtered out, dried and solidified under reduced pressure. The resulting solid was purified by reversed phase column chromatography, and the resulting dried residue was washed with acetonitrile, dried and solidified under reduced pressure to obtain the title compound (71 mg) as a white solid.

¹H-NMR (0.1M Na₂CO₃ in D₂O) 5: 7.84-7.76 (1H, m), 7.30-7.20 (1H, m), 6.91-6.89 (1H, m), 6.12-6.01 (1H, m), 5.02-4.89 (1H, m), 4.58-3.76 (4H, m), 2.59 (2H, m), 0.55 (2H, m).

LCMS: [M+H]⁺/Rt=388.12/0.410 min^(C)

Example 41; 7-({1-[2-amino-2-(1H-imidazol-4-yl)propanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

A reaction, work-up, and purification were performed using the compound of Reference Example 39 (153 mg, 0.189 mmol) as the starting material by the same method described in Example 36 to obtain the title compound (42 mg) as a white solid.

¹H-NMR (0.1 M Na₂CO₃ in D₂O) δ: 7.77 (1H, m), 7.18 (1H, m), 6.83 (1H, m), 5.91 (1H, m), 4.35 (1H, m), 3.95-4.20 (2H, m), 3.30-3.51 (2H, m), 2.57 (2H, m), 1.63 (3H, s), 0.36 (2H, m).

LCMS: [M+H]⁺/Rt=401.12/0.422 min^(C)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 56 and 58 as the starting materials by the same method described in Example 37 to obtain Example compounds 42 and 43, respectively. However, if hydrochloride is the final product (Example 43), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-5 Starting Example material Structural formula NMR and/or LCMS 42 Reference Example 56

LCMS: [M + H]⁺/Rt = 401.10/0.451 min^(C) 43 Reference Example 58

LCMS: [M + H]⁺/Rt = 399.10/0.493 min^(C) ¹H-NMR (CD₃OD) δ: 8.61 (1H, s), 7.21 (1H, s), 7.17 (1H, d, J = 7.9 Hz), 6.34 (1H, d, J = 7.9 Hz). 5.18- 5.15 (1H, m), 4.70-4.67 (2H, m), 4.34- 4.21 (2H, m), 2.70 (2H, t, J = 7.6 Hz), 2.67 (3H, s), 1.05 (2H, t, J = 7.6 Hz).

The names of the compounds of Examples 42 and 43 are described below.

-   8-({(3S)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 42) -   2-hydroxy-7-([1-(4-hydroxy-6-methylpyridine-3-carbonyl)azetidin-3-yl]oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 43)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 38, 48, 49, 55, 57, 63, 64, and 71 as the starting materials by the same method described in Example 38 to obtain each of the following Example compounds 44 to 51. However, if hydrochloride is the final product (Examples 46 and 51), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-6 Starting Example material Structural formula NMR and/or LCMS 44 Reference Example 57

LCMS: [M + H]⁺/Rt = 401.20/0.393 min^(C) 45 Reference Example 48

LCMS: [M + H ]⁺/Rt = 445.2/0.82 min^(B) ¹H-NMR (CD₃OD) δ: 7.57 (1H, s), 7.08 (1H, s), 6.70 (1H, d, J = 8.1 Hz), 5.90 (1H, d, J = 8.1 Hz), 4.98-4.90 (1H, m), 4.62-3.93 (7H, m), 2.55 (2H, t, J = 5.4 Hz), 0.44 (2H, t, J = 5.4 Hz). 46 Reference Example 49

LCMS: [ M + H ]⁺/Rt = 444.3/0.52 min^(B) ¹H-NMR (CD₃OD) δ: 9.01 (1H, s), 7.88 (1H, s), 7.15 (1H, d, J = 8.1 Hz), 6.35- 6.28 (1H, m), 5.55 (1H, d, J = 16.2 Hz), 5.20-4.97 (3H, m), 4.77-3.72 (4H, m), 2.69 (2H, t, J = 8.1 Hz), 1.05 (2H, t, J = 8.1 Hz). 47 Reference Example 63

LCMS: [M + H]⁺/Rt = 398.3/0.82 min^(B) ¹H-NMR (CD₃OD) δ: 8.59 (1H, s), 8.50-8.47 (1H, m), 7.90-7.84 (1H, m), 7.47-7.41 (1H, m), 6.67 (1H, d, J = 8.1 Hz), 5.89-5.85 (1H, m), 5.01-4.94 (1H, m), 4.73-3.73 (5H, m), 2.54 (2H, t, J = 5.4 Hz), 0.41 (2H, t, J = 5.4 Hz).

TABLE 3-7 48 Reference Example 64

LCMS: [M + H]⁺/Rt = 401.3/0.92 min^(B) ¹H-NMR (CD₃OD) δ: 7.61-7.59 (1H, m), 7.47 (1H, s), 6.68 (1H, d, J = 8.1 Hz), 5.90-5.86 (1H, s), 5.00-4.94 (1H, m), 4.64-3.96 (5H, m), 3.86 (3H, s), 2.55 (2H, t, J = 8.1 Hz), 0.41 (2H, t, J = 8.1 Hz). 49 Reference Example 55

LCMS: [M + H]⁺/Rt = 401.05/0.442 min^(C) 50 Reference Example 38

LCMS: [M + H]⁺/RT = 401.16/0.387 min^(C) ¹H-NMR (D₂O) δ: 6.62 (1H, d, J = 12.8 Hz), 6.48 (1H, d, J = 7.9 Hz), 5.61 (1H, d, J = 7.9 Hz), 4.61-4.49 (2H, m), 4.30-4.26 (1H, m), 4.05-3.94 (1H, m), 3.90-3.81 (1H, m), 3.70-3.63 (1H, m), 2.18 (2H, t, J = 6.4 Hz), 1.94 (3H, d, J = 4.3 Hz), 0.00 (2H, t, J = 6.1 Hz). 51 Reference Example 71

LCMS: [M + H]⁺/Rt = 404.2/0.95 min^(B) ¹H-NMR (CD₃OD) δ: 9.13-9.10 (1H, m), 7.92-7.91 (1H, m), 7.13 (1H, d, J = 8.2 Hz), 6.27 (1H, d, J = 8.2 Hz), 5.50- 5.49 (1H, m), 5.12-5.03 (1H, m), 4.73- 3.62 (4H, m), 2.68 (2H, t, J = 8.1 Hz), 1.05 (2H, t, J = 8.1 Hz).

The names of the compounds of Examples 44 to 51 are described below.

-   8-({1-[amino(1-methyl-1H-imidazol-5-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6,7,9-triene-7-carboxylic     acid disodium salt (Example 44) -   8-[(1-{amino[1-(carboxymethyl)-1H-imidazol-4-yl)acetyl)azetidin-3-yl)oxy]-4,4-dihydroxy-S-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic     acid trisodium salt (Example 45) -   7-[(1-{amino[1-(2-amino-2-oxoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 46) -   8-({1-[amino(pyridin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 47) -   8-({1-[amino(1-methyl-1H-pyrazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 48) -   8-({(3R)-1-[amino(1H-imidazol-4-yl)acetyl]pyrrolidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 49) -   8-({1-[amino(2-methyl-1H-imidazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 50) -   7-({1-[amino(1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 51)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 106 to 108 as the starting materials by the same method described in Example 38 to obtain the following Example compounds 52 to 54, respectively.

TABLE 3-8 Starting Example material Structural formula NMR and/or LCMS 52 Reference Example 106

LCMS: [M + H]⁺/Rt = 394.4/1.20 min^(B) ¹H-NMR (CD₃OD) δ: 8.07 (1H, s), 7.87 (1H, s), 7.12 (1H, d, J = 8.1 Hz), 6.23 (1H, d, J = 8.1 Hz), 4.93-4.87 (1H, m), 4.34-4.26 (2H, m), 3.91-3.88 (2H, m), 2.66 (2H, t, J = 8.1 Hz), 1.04 (2H, t, J = 8.1 Hz). 53 Reference Example 107

LCMS: [M + H]⁺/Rt = 405.3/1.41 min^(B) ¹H-NMR (CD₃OD) δ: 9.00 (1H, s), 8.87 (1H, d, J = 5.4 Hz), 8.31 (1H, d, J = 8.1 Hz), 7.74-7.00 (1H, m), 7.10 (1H, d, J = 8.1 Hz), 6.22 (1H, d, J = 8.1 Hz), 4.97-4.65 (1H, m), 4.33-4.27 (2H, m), 3.83-3.77 (2H, m), 2.65 (2H, t, J = 8.1 Hz), 1.02 (2H, t, J = 8.1 Hz). 54 Reference Example 108

LCMS: [M + H]⁺/Rt = 421.3/1.30 min^(B) ¹H-NMR (CD₃OD) δ: 8.46-8.36 (1H, m), 8.06 (1H, dd, J = 5.4 Hz, 2.7 Hz), 7.70-7.57 (2H, m), 7.12 (1H, d, J = 8.1 Hz), 6.28 (1H, d, J = 8.1 Hz), 5.08- 5.00 (1H, m), 4.61-4.55 (2H, m), 4.33- 4.26 (2H, m), 2.65 (2H, t, J = 8.1 Hz), 1.05 (2H, t, J = 8.1 Hz).

The names of the compounds of Examples 52 to 54 are described below.

-   2-hydroxy-7-{[1-(1H-imidazole-4-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 52) -   2-hydroxy-7-{[1-(pyridine-3-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 53) -   2-hydroxy-7-{[1-(1-oxo-1λ⁵-pyridine-2-sulfonyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 54)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 40, 43 to 47, 50, 51, 59, 65, 66, 69, 70, 114 to 116, and 127 as the starting materials by the same method described in Example 4 to obtain the following Example compounds 55 to 71 (corresponding starting materials are not in order). However, if a free form is the final product (Examples 57, 61, 64, 65: 67, and 71), the free form was obtained from purifying the compound without sodium hydroxide treatment. If hydrochloride is the final product (Examples 58, 62, and 63), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-9 Starting Example material Structural formula NMR and/or LCMS 55 Reference Example 65

LCMS: [M + H]⁺/Rt = 404.4/1.03 min^(B) ¹H-NMR (CD₃OD) δ: 6.69 (1H, d, J = 8.2 Hz), 6.31 (1H, s), 5.90 (1H, d, J = 8.2 Hz), 5.00-4.86 (1H, m), 4.63-4.47 (1H, m), 4.39-4.21 (2H, m), 4.08-3.96 (1H, m), 3.41-3.35 (2H, m), 2.63-2.49 (2H, m), 0.48-0.35 (2H, m). 56 Reference Example 66

LCMS: [M + H]+/Rt = 390.2/1.16 min^(B) ¹H-NMR (CD₃OD) δ: 7.24 (1H, s), 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 4.95-4.90 (2H, m), 4.62-4.56 (1H, m), 4.47-4.41 (1H, m), 4.16-4.12 (1H, m), 2.59-2.54 (2H, m), 0.47-0.42 (2H, m). 57 Reference Example 69

LCMS: [M + H]⁺/Rt = 373.22/1.62 min^(D) ¹H-NMR (CD₃OD) δ: 8.11 (1H, d, J = 1.1 Hz), 7.91 (1H, s), 7.22-7.13 (1H, m), 6.40-6.28 (1H, m), 5.32 (2H, s), 5.16-5.10 (1H, m), 4.74-4.66 (1H, m), 4.50-4.42 (1H, m), 4.37-4.31 (1H, m), 4.10-4.02 (1H, m), 2.77-2.62 (2H, m), 1.10-1.01 (2H, m).

TABLE 3-10 58 Reference Example  70

LCMS: [M + H]⁺/Rt = 415.2/0.52 min^(B) ¹H-NMR (CD₃OD) δ: 9.04 (1H, s), 7.63 (1H, s), 7.18 (1H, d, J = 8.1 Hz), 6.37 (1H, d, J = 8.1 Hz), 5.15-5.12 (1H, m), 4.79-4.73 (1H, m), 4.60 (2H, t, J = 5.4 Hz), 4.54-4.33 (2H, m), 4.18-4.02 (1H, m), 3.79 (2H, s), 3.53 (2H, t, J = 5.4 Hz), 2.71-2.65 (2H, m), 1.10-1.04 (2H, m). 59 Reference Example  40

LCMS: [M + H]⁺/Rt = 358.2/0.90 min^(B) ¹H-NMR (CD₃OD) δ: 7.81 (1H, s), 7.67 (1H, s), 6.93 (1H, d, J = 8.1 Hz), 6.11 (1H, d, J = 8.1 Hz), 5.14-5.03 (1H, m), 4.92-4.73 (1H, m), 4.59-4.52 (2H, m), 4.24-4.19 (1H, m), 2.60 (2H, t, J = 8.1 Hz), 0.40 (2H, t, J = 8.1 Hz). 60 Reference Example 127

LCMS: [M + H]⁺/Rt = 358.1/1.17 min^(B) ¹H-NMR (CD₃OD) δ: 7.28 (2H, s), 6.93 (1H, d, J = 8.1 Hz), 6.11 (1H, d, J = 8.1 Hz), 5.16-5.09 (1H, m), 5.04-4.71 (1H, m), 4.67-4.55 (2H, m), 4.27-4.21 (1H, m), 2.61 (2H, t, J = 8.1 Hz), 0.41 (2H, t, J = 8.1 Hz). 61 Reference Example  43

LCMS: [M + H]⁺/Rt = 403.17/1.58 min^(D) ¹H-NMR (CD₃OD) δ: 8.06 (1H, s), 7.21-7.12 (1H, m), 6.41-6.27 (1H, m), 5.31 (2H, s), 5.16-5.10 (1H, m), 4.77-4.67 (3H, m), 4.50-4.42 (1H, m), 4.38-4.31 (1H, m), 4.10-4.02 (1H, m), 2.74-2.63 (2H, m), 1.06 (2H, t, J = 7.7 Hz). 62 Reference Example 114

LCMS: [M + H]⁺/Rt = 416.30/1.25 min^(D) ¹H-NMR (CD₃OD) δ: 8.12 (1H, s), 7.23-7.10 (1H, m), 6.41-6.29 (1H, m), 5.30 (2H, s), 5.18-5.10 (1H, m), 4.78-4.71 (1H, m), 4.50-4.43 (1H, m), 4.40-4.28 (3H, m), 4.11-4.03 (1H, m), 2.79-2.65 (5H, m), 1.10-1.02 (2H, m). 63 Reference Example 115

LCMS: [M + H]⁺/Rt = 471.27/1.15 min^(D) ¹H-NMR (CD₃OD) δ: 8.29 (1H, s), 7.21-7.13 (1H, m), 6.40-6.30 (1H, m), 5.34 (2H, s), 5.19-5.13 (1H, m), 4.79-4.73 (1H, m), 4.64 (2H, s), 4.50-4.45 (1H, m), 4.41-4.36 (1H, m), 4.11-4.04 (1H, m), 3.71-3.54 (8H, m), 2.74-2.66 (2H, m), 1.10-1.03 (2H, m).

TABLE 3-11 64 Reference Example 116

LCMS: [M + H]⁺/Rt = 417.26/1.56 min^(D) ¹H-NMR (CD₃OD) δ: 8.10 (1H, s), 7.23-7.13 (1H, m), 6.43-6.28 (1H, m), 5.36 (2H, s), 5.19-5.12 (1H, m), 4.76-4.68 (1H, m), 4.52-4.44 (1H, m), 4.38-4.32 (1H, m), 4.13-4.06 (1H, m), 3.90-3.78 (2H, m), 3.04-2.95 (2H, m), 2.78-2.65 (2H, m), 1.12-1.00 (2H, m). 65 Reference Example  44

LCMS: [M + H]⁺/Rt = 403.35/1.44 min^(D) ¹H-NMR (CD₃OD) δ: 7.77 (1H, s), 7.23-7.12 (1H, m), 6.44-6.25 (1H, m), 5.35-5.31 (2H, m), 5.16-5.12 (1H, m), 4.76-4.70 (3H, m), 4.51-4.44 (1H, m), 4.40-4.32 (1H, m), 4.11-4.04 (1H, m), 2.77-2.65 (2H, m), 1.10-1.03 (2H, m). 66 Reference Example  45

LCMS: [M + H]⁺/Rt = 416.34/1.12 min^(D) ¹H-NMR (D₂O) δ: 7.76 (1H, s), 6.89 (1H, d, J = 8.0 Hz), 6.06 (1H, d, J = 8.0 Hz), 5.33-5.22 (2H, m), 5.12-5.06 (1H, m), 4.74-4.67 (1H, m), 4.49-4.36 (2H, m), 4.16-4.10 (1H, m), 3.79 (2H, s), 2.62-2.54 (2H, m), 2.34 (3H, s), 0.41-0.33 (2H, m). 67 Reference Example  59

LCMS: [M + H]⁺/Rt = 373.35/1.59 min^(D) ¹H-NMR (CD₃OD) δ: 8.19 (1H, s), 7.21-7.07 (1H, m), 6.42-6.21 (1H, m), 5.09-5.05 (1H, m), 4.72-4.65 (1H, m), 4.43-4.36 (1H, m), 4.35-4.28 (1H, m), 4.03-3.95 (1H, m), 3.84 (2H, s), 2.71-2.61 (2H, m), 1.06-0.97 (2H, m). 68 Reference Example  46

LCMS: [M + H]⁺/Rt = 431.12/1.71 min^(D) ¹H-NMR (D₂O) δ: 7.84 (1H, d, J = 6.9 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.09 (1H, d, J = 8.0 Hz), 5.33-5.22 (2H, m), 5.12-5.05 (1H, m), 4.72-4.66 (1H, m), 4.50-4.43 (1H, m), 4.43-4.37 (1H, m), 4.16-4.10 (1H, m), 3.64 (2H, s), 2.64-2.56 (2H, m), 0.51-0.42 (2H, m). 69 Reference Example  47

LCMS: [M + H]⁺/Rt = 431.16/1.44 min^(D) ¹H-NMR (D₂O) δ: 7.86 (1H, s), 6.89 (1H, d, J = 8.0 Hz), 6.06 (1H, d, J = 8.0 Hz), 5.06-5.00 (3H, m), 4.70-4.65 (1H, m), 4.44-4.35 (2H, m), 4.11-4.05 (1H, m), 3.80-3.67 (2H, m), 2.62-2.55 (2H, m), 0.41-0.34 (2H, m). 70 Reference Example  50

LCMS: [M + H]⁺/R = 388.35/0.93 min^(D) ¹H-NMR (D₂O) δ: 7.77-7.72 (1H, m), 6.92-6.34 (1H, m), 6.05-5.93 (1H, m), 5.03-4.85 (2H, m), 4.64-3.91 (4H, m), 2.62-2.49 (2H, m), 0.49-0.37 (2H, m).

TABLE 3-12 71 Reference Example 51

LCMS: [M + H]⁺/R = 418.13/2.03 min^(D) ¹H-NMR (CD₃OD) δ: 8.92 (1H, s), 7.22-7.13 (1H, m), 6.40-6.12 (1H, m), 5.41-5.34 (2H, m), 5.19-5.12 (1H, m), 4.78-4.71 (1H, m), 4.52-4.45 (1H, m), 4.44-4.37 (1H, m), 4.13-4.06 (1H, m), 2.76-2.66 (2H, m), 1.11-1.02 (2H, m).

The names of the compounds of Examples 55 to 71 are described below.

-   8-({1-[(2-amino-1,3-thiazol-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 55) -   8-{[1-(2-amino-1,3-thiazole-4-carbonyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 56) -   2-hydroxy-7-({1-[(1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 57) -   7-[(1-{[1-(2-aminoethyl)-1H-imidazol-4-yl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 58) -   4,4-dihydroxy-8-{[1-(1H-imidazole-4-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 59) -   4,4-dihydroxy-8-{[1-(1H-imidazole-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 60) -   2-hydroxy-7-[(1-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 61) -   2-hydroxy-7-{[1-({4-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 62) -   2-hydroxy-7-{[1-({4-[(piperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid dihydrochloride (Example 63) -   2-hydroxy-7-[(1-{[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 64) -   2-hydroxy-7-[(1-{[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 65) -   4,4-dihydroxy-8-{[1-({5-[(methylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 66) -   2-hydroxy-7-({1-[(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 67) -   8-[(1-{([4-(carboxymethyl)-1H-1,2,3-triazol-1-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic     acid trisodium salt (Example 68) -   8-[(1-{[1-(carboxymethyl)-1H-1,2,3-triazol-4-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid trisodium salt (Example 69) -   8-({1-[amino(1H-1,2,3-triazol-4-yl)acetyl]azetidin-3-yl}oxy-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 70) -   2-hydroxy-7-({1-[(4-nitro-1H-1,2,3-triazol-1-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 71)

Example 72; 7-({1-(amino(3,4-dihydroxyphenyl)acetyl)azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

Example 72-1: tert-butyl 6-[(1-{[(tert-butoxycarbonyl)amino](3,4-dihydroxyphenyl)acetyl}azetidin-3-yl)oxy]-2-[(tert-butoxycarbonyl)oxy]-3-{2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}benzoate

Palladium on carbon (19 mg, Pd content: 10%, wetted with ca. 55% water) was added to a methanol solution (2 mL) of the compound of Reference Example 67 (190 mg, 0.187 mmol), and the reaction mixture was stirred for 2.5 hours under a hydrogen atmosphere at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated to obtain the title compound (143 mg) as a colorless amorphous compound.

¹H-NMR (CDCl₃) δ: 7.19 (1H, d, J=8.1 Hz), 6.93 (1H, d, J=16.2 Hz), 6.82-6.71 (2H, m), 6.32 (1H, d, J=8.1 Hz), 5.99 (1H, br), 5.77-5.65 (1H, m), 5.08-3.80 (7H, m), 2.63-2.56 (2H, m), 2.36-2.27 (1H, m), 2.19-2.12 (1H, m), 2.04-1.99 (1H, m), 1.89-1.77 (2H, m), 1.63-1.39 (27H, m), 1.35 (3H, s), 1.28 (3H, s), 1.12-1.00 (3H, m), 0.83 (3H, s).

LCMS: [M+H]⁺/Rt=837.7/2.83 min^(B)

Example 72: 7-({1-[amino(3,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

Phenylboronic acid (18.7 mg, 0.153 mmol), hexane (1.5 mL), and 4 N hydrochloric acid/dioxane solution (0.76 mL) were added to an acetonitrile solution (1.5 mL) of the compound of Example 72-1 (128 mg, 0.153 mmol), and the reaction mixture was stirred for 17 hours at room temperature. The reaction solution was allowed to stand. The supernatant (top layer) was removed, and hexane (5 mL) was added to the remaining bottom layer. After stirring and then allowing it to stand, the supernatant was removed. This was repeated 5 times. Diethyl ether (5 mL) was added to the bottom layer. After stirring and then allowing it to stand, the supernatant (top layer) was removed. This was repeated 3 times. The resulting residue was dried under reduced pressure. Since an intermediate (Boc-undeprotected form of the title compound) was also found in the resulting residue, a 4 N hydrochloric acid/dioxane solution (3.0 mL) was further added. The reaction mixture was stirred for 21 hours at room temperature, and the reaction solution was concentrated. The resulting residue was dissolved in methanol (1.5 mL) and purified by reversed phase column chromatography to obtain the title compound (19.3 mg) as a light yellow solid.

¹H-NMR (CD₃OD) δ: 7.25-7.05 (1H, m), 6.91-6.79 (3H, m), 6.25-6.00 (1H, m), 5.09-4.94 (1H, m), 4.63-3.98 (3H, m), 3.76-3.53 (2H, m), 2.81-2.39 (2H, m), 1.16-0.51 (2H, m).

LCMS: [M+H]⁺/Rt=429.2/0.96 min^(B)

Example 73: 7-({1-[amino(2,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

Example 73-1:7-[(1-{amino[2,4-bis(benzyloxy)phenyl]acetyl}azetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

A reaction, work-up, and purification were performed using the compound of Reference Example 68 (195 mg, 0.192 mmol) as the starting material by the same method described in Example 72 to obtain the title compound (78 mg) as a colorless solid.

¹H-NMR (CD₃OD) δ: 7.45-7.26 (11H, m), 7.14-7.11 (1H, m), 6.87-6.79 (1H, m), 6.74-6.65 (1H, m), 6.16 (1H, brs), 5.25-5.04 (5H, m), 5.03-4.91 (1H, m), 4.48-3.90 (31H, m), 3.77-3.60 (1H, m), 2.73-2.64 (2H, m), 1.09-1.02 (2H, m).

LCMS: [M+H]⁺/Rt=609.6/1.80 min^(B)

Example 73: 7-({1-([amino(2,4-dihydroxyphenyl)acetyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid hydrochloride

Palladium on carbon (13 mg, Pd content: 10%, wetted with ca. 55% water) was added to a THF solution (25 mL) of the compound of Example 73-1 (65.1 mg, 0.101 mmol), and the reaction mixture was stirred for 2.5 hours under a hydrogen atmosphere at room temperature. Subsequently, methanol (0.25 mL) was added, and the reaction mixture was stirred for 4 days at room temperature. Subsequently, palladium on carbon (13 mg) was added, and the reaction mixture was stirred for 1 day at room temperature. Palladium on carbon (13 mg) was further added, and the reaction mixture was stirred for 5 days at room temperature. The reaction solution was filtered through cellulose. The filtered substance was washed with methanol, and the combined filtrate was concentrated. The resulting residue was dissolved in methanol (2 mL) and purified by reversed phase column chromatography to obtain the title compound (9.0 mg) as a colorless solid.

¹H-NMR (CD₃OD) δ: 7.13-5.98 (5H, m), 5.23-5.19 (1H, m), 5.04-4.79 (1H, m), 4.51-3.47 (4H, m), 2.85-1.93 (2H, m), 1.16-0.65 (2H, m).

LCMS: [M+H]⁺/Rt=429.2/0.94 min^(B)

Example 74: 7-{[1-(S-benzyl-D-cysteinyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine 8-carboxylic acid trifluoroacetate

Trifluoroacetic acid (3.3 mL) was added to the compound of Reference Example 72 (106 mg), and the reaction mixture was stirred for 8 hours at room temperature. The reaction mixture was dried and solidified under reduced pressure. The resulting dried residue was purified by reversed phase column chromatography. The resulting dried residue was washed with acetonitrile, dried and solidified under reduced pressure to obtain the title compound (24.6 mg) as a white solid.

LCMS: [M+H]⁺/Rt=865.61/1.332 min^(A)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 73 and 74 as the starting materials by the same method described in Reference Example 74 to obtain the following Example compounds 75 and 76, respectively.

The names of the compounds of Examples 75 and 76 are described below.

-   7-[(1-D-cysteinylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 75) -   2-hydroxy-7-{[1-(3-sulfanyl-D-valyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 76)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 42, 52, 76 to 78, and 109 to 113 as the starting materials by the same method described in Example 38 to obtain the following Example compounds 77 to 86 (corresponding starting materials are not in order). However, if a free form is the final product (Example 83), the free form was obtained from purifying the compound without sodium hydroxide treatment. If hydrochloride is the final product (Examples 79, 80, 82, and 84 to 86), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-14 Starting Example material Structural formula NMR and/or LCMS 77 Reference Example  76

LCMS: [M + H]⁺/Rt = 379.1/0.76 min^(B) ¹H-NMR (CD₃OD) δ: 6.71 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.93 (1H, m), 4.73-4.61 (1H, m), 4.37-4.27 (2H, m), 4.05-4.01 (1H, m), 3.79-3.71 (1H, m), 2.59-2.47 (3H, m), 2.38-2.25 (1H, m), 0.41 (2H, t, J = 8.1 Hz). 78 Reference Example  77

LCMS: [M + H]⁺/Rt = 406.3/1.00 min^(B) ¹H-NMR (CD₃OD) δ: 6.73 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5 05-4-95 (1H, m), 4-75-4.53 (1H, m), 4.48-4.28 (3H, m), 4.08-3.98 (1H, m), 3.66-3.42 (1H, m), 2.57 (2H, d, J = 8.1 Hz), 1.32-1.25 (6H, m), 0.45 (2H, t, J = 8.1 Hz). 79 Reference Example  42

LCMS: [M + H]⁺/Rt = 378.2/0.81 min^(B) ¹H-NMR (CD₃OD) δ: 7.21-7.11 (1H, m), 6.38-6.10 (1H, m), 5.16-4.98 (1H, m), 4.78-4.64 (1H, m), 4.54-4.26 (3H, m), 4.12-4.02 (1H, m), 2.90-2.54 (4H, m), 1.10-0.64 (2H, m). 80 Reference Example 109

LCMS: [M + H]⁺/Rt = 378.2/0.58 min^(B) ¹H-NMR (CD₃OD) δ: 7.18 (1H, d, J = 8.1 Hz), 6.35 (1H, d, J = 8.1 Hz), 5.17-5.07 (1H, m), 4.79-4.72 (1H, m), 4.55-4.27 (3H, m), 4.12-4.01 (1H, m), 2.92-2.64 (4H, m), 1.07 (2H, t, J = 8.1 Hz). 81 Reference Example  78

LCMS: [M + H]⁺/Rt = 379.1/0.56 min^(B) ¹H-NMR (CD₃OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.73-4.61 (1H, m), 4.37-4.27 (2H, m), 4.06-4.00 (1H, m), 3.80-3.72 (1H, m), 2.59-2.47 (3H, m), 2.39-2.26 (1H, m), 0.44 (2H, t, J = 8.1 Hz). 82 Reference Example  52

LCMS: [M + H]⁺/Rt = 351.0/0.48 min^(B) ¹H-NMR (CD₃OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.35 (1H, d, J = 8.1 Hz), 5.18-5.09 (1H, m), 4.79-4.70 (1H, m), 4.55-4.33 (2H, m), 4.12-4.02 (2H, m), 3.92-3.84 (1H, m), 3.80-3.73 (1H, m), 2.70 (2H, t, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz).

TABLE 3-15 83 Reference Example 110

LCMS: [M + H]⁺/Rt = 363.0/0.97 min^(B) ¹H-NMR (CD₃OD) δ: 7.18-7.09 (1H, m), 6.33-6.09 (1H, m), 5.10-5.02 (1H, m), 4.67-4.62 (1H, m), 4.40-4.34 (1H, m), 4.28-4.23 (1H, m), 3.99-3.94 (1H, m), 2.72-2.38 (6H, m), 1.09-0.91 (2H, m). 84 Reference Example 111

LCMS: [M + H]⁺/Rt = 392.1/0.79 min^(B) ¹H-NMR (CD₃OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.40-6.30 (1H, m), 5.17-5.08 (1H, m), 4.77-4.71 (1H, m), 4.54-4.31 (2H, m), 4.14-4.02 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 2.48-2.42 (2H, m), 2.15-2.00 (2H, m), 1.06 (2H, t, J = 8.1 Hz). 85 Reference Example 113

LCMS: [M + H]⁺/Rt = 393.1/0.47 min^(B) ¹H-NMR (CD₃OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.35 (1H, d, J = 8.2 Hz), 5.17-5.08 (1H, m), 4.81-4.72 (1H, m), 4.55-4.30 (2H, m), 4.17-4.03 (2H, m), 3.60-3.40 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz). 86 Reference Example 112

LCMS: [M + H]⁺/Rt = 392.1/0.86 min^(B) ¹H-NMR (CD₃OD) δ: 7.18 (1H, d, J = 8.2 Hz), 6.39-6.30 (1H, m), 5.18-5.09 (1H, m), 4.80-4.72 (1H, m), 4.55-4.32 (2H, m), 4.21-4.03 (2H, m), 3.60-3.42 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 2.01-1.98 (3H, m), 1.06 (2H, t, J = 8.1 Hz).

The names of the compounds of Examples 77 to 86 are described below.

-   8-({1-[(2S)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid trisodium salt (Example 77) -   8-{[1-(D-alanyl-D-alanyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 78) -   7-[(1-L-asparaginylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 79) -   7-[(1-D-asparaginylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 80) -   8-({1-[(2R)-2-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid trisodium salt (Example 81) -   2-hydroxy-7-[(1-D-serylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 82) -   7-{[1-(4-amino-4-oxobutanoyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 83) -   7-[(1-D-glutaminylazetidin-3-yl)oxy]-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 84) -   7-({1-[3-(carbamoylamino)-D-alanyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 85) -   1-(3-acetamido-D-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 86)

The following Example compounds 87 to 89 (corresponding starting materials are not in order) were obtained by performing a reaction and work-up using the compounds of Reference Examples 53, 54, and 75 as the starting materials by the same method described in Example 4, and purifying the compounds by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-16 Starting Example material Structural formula NMR and/or LCMS 87 Reference Example 54

LCMS: [M + H]+/Rt = 406.36/1.38 min^(D) ¹H-NMR (CD₃OD) δ: 7.22-7.12 (1H, m), 6.41-6.28 (1H, m), 5.17-5.07 (1H, m), 4.83-4.68 (1H, m), 4.54-4.24 (3H, m), 4.13-4.00 (1H, m), 3.11-2.77 (8H, m), 2.75-2.64 (21-I, m), 1.10-1.00 (2H, m). 88 Reference Example 53

LCMS: [M + H]+/Rt = 392.19/1.43 min^(D) ¹H-NMR (CD₃OD) δ: 7-24-7.10 (1H, m), 6.46-6.23 (1H, m), 5.18-5.09 (1H, m), 4.79-4.68 (1H, m), 4.57-4.27 (3H, m), 4.22-3.98 (1H, m), 2.85-2.61 (7H, m), 1.10-1.03 (2H, m). 89 Reference Example 75

LCMS: [M + H]+/Rt = 351.21/0.97 min^(D) ¹H-NMR (CD₃OD) δ: 7.20-7.14 (1H, m), 6.40-6.28 (1H, m), 5.17-5.09 (1H, m), 4.78-4.70 (1H, m), 4.56-4.41 (1H, m), 4.39-4.32 (1H, m), 4.14-4.02 (2H, m), 3.92-3.85 (1H, m), 3.81-3.74 (1H, m), 2.75-2.65 (2H, m), 1.12-1.03 (2H, m).

The names of the compounds of Examples 87 to 89 are described below.

-   7-{[1-(N,N-dimethyl-D-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 87) -   2-hydroxy-7-{[1-(N-methyl-D-asparaginyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 88) -   2-hydroxy-7-[(1-L-serylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborine-8-carboxylic     acid hydrochloride (Example 89)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 60, 62, 79 to 81, 124, and 125 as the starting materials by the same method described in Example 37 to obtain the following Example compounds 90 to 96 (corresponding starting materials are not in order). However, if a free form is the final product (Example 91), the free form was obtained from purifying the compound without sodium hydroxide treatment. If hydrochloride is the final product (Examples 90, 92, and 93), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-17 Exam- Starting ple material Structural formula NMR and/or LCMS 90 Reference Example  79

LCMS: [M + H]+/Rt = 377.4/0.425 min^(C) ¹H-NMR (CD₃OD) δ: 7.16 (1H, d, J = 8.5 Hz), 6.34 (1H, d, J = 8.5 Hz), 5.15 (1H, s), 4.72-4.66 (1H, m), 4.54-4.48 (4H, m), 4.32-4.25 (1H, m), 4.13-4.05 (1H, m), 3.39-3.33 (1H, m), 2.72-2.67 (2H, m), 2.61-2.57 (1H, m), 2.09-2.05 (1H, m), 1.03-1.00 (2H, m). 91 Reference Example  80

LCMS: [M + H]+/Rt = 429.1/0.537 min^(C) ¹H-NMR (CD₃OD) δ: 7.19-7.17 (1H, m), 636-6.33 (1H, m), 5.22-5-11 (2H, m), 4.58-4.50 (2H, m), 4.36-4.33 (1H, m), 4.13-4.11 (1H, m), 3.68-3.66 (1H, m), 3.52-3.50 (2H, m), 2.84-2.81 (1H, m), 2.70 (2H, t, J = 7.9 Hz), 2.11-2.09 (1H, m), 1.06 (2H, t, J = 7.6 Hz). 92 Reference Example  81

LCMS: [M + H]+/Rt = 379.09/0.453 min^(C) 93 Reference Example  60

LCMS: [M + H]+/Rt = 375.01/0.304 min^(A) ¹H-NMR (CD₃OD) δ: 7.16 (1H, d, J = 7.3 Hz), 6.35-6.33 (1H, m), 5.08-5.06 (1H, m), 4.62-4.59 (1H, m), 4.39-4.37 (1H, m), 4.22 (1H, d, J = 9.8 Hz), 3.97 (1H, d, J = 11.0 Hz), 3.52 (1H, t, J = 9.8 Hz), 3.38-3.35 (1H, m), 3.25-3.23 (1H, m), 2.93 (1H, t, J = 10.4 Hz), 2.70-2.68 (3H, m), 2.48-2.45 (1H, m), 2.39-2.35 (1H, m), 2.26-2.24 (1H, m), 1.73-1.68 (1H, m), 1.07 (2H, t, J = 7.9 Hz). 94 Reference Example 124

LCMS: [M + H]+/Rt = 466.23/0.486 min^(C) ¹H-NMR (D₂O) δ: 6.51 (1H, d, J = 8.5 Hz), 5.67 (1H, dd, J = 8.5, 2.7 Hz), 4.64-4.59 (1H, m), 4.22-4.16 (1H, m), 4.00-3.84 (3H, m), 3.65 (1H, dd, J = 10.7, 3.4 Hz), 2.87-2.82 (1H, m), 2.68 (3H, d, J = 3.1 Hz), 2.57 (3H, d, J = 8.5 Hz), 2.49-2.44 (1H, m), 2.23-2.14 (4H, m), 1.99-1.90 (2H, m), 1.07-1.03 (1H, m), 0.00 (2H, t, J = 7.0 Hz).

TABLE 3-18 95 Reference Example 125

LCMS: [M + H]⁺/Rt = 466.28/0.482 min^(C) ¹H-NMR (D₂O) δ: 6.51 (1H, d, J = 7.9 Hz), 5.67 (1H, dd, J = 7.9, 2.4 Hz), 4.64-4.59 (1H, m), 4.19 (1H, dd, J = 15.9, 9.2 Hz), 4.00-3.84 (3H, m), 3.64 (1H, dd, J = 11.0, 3.4 Hz), 2.90-2.85 (1H, m), 2.68 (3H, d, J = 3.7 Hz), 2.57 (3H, d, J = 7.9 Hz), 2.52-2.46 (1H, m), 2.23-2.17 (4H, m), 1.98-1.92 (2H, m), 1.07 (1H, dd, J = 8.9, 4.0 Hz), 0.00 (2H, t, J = 7.0 Hz). 96 Reference Example  62

LCMS: [M + H]⁺/Rt = 393.10/0.477 min^(C) ¹H-NMR (D₂O) δ: 6.49 (1H, d, J = 7.9 Hz), 5.67 (1H, d, J = 7.9 Hz), 4.98 (1H, dq, J = 53.1, 4.3 Hz), 4.64-4.58 (1H, m), 4.42-4.39 (1H, m), 4.20-4.15 (1H, m), 3.97 (1H, dd, J = 10.4, 6.1 Hz), 3.88 (1H, dd, J = 10.4, 3.7 Hz), 3.64 (1H, dd, J = 11.0, 3.1 Hz), 3.41-3.31 (1H, m), 3.07 (1H, dt, J = 20.0, 13.0 Hz), 2.84-2.67 (1H, m), 2.29-2.22 (1H, m), 2.18 (2H, t, J = 7.0 Hz), 2.15-2.02 (1H, m), 1.59-1.47 (1H, m), 0.00 (2H, t, J = 7.0 Hz).

The names of the compounds of Examples 90 to 96 are described below.

-   2-hydroxy-7-{[1-(4-hydroxyprolyl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 90) -   2-hydroxy-7-({1-[(4R)-4-(trifluoromethyl)-D-prolyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid (Example 91) -   7-({1-[(4S)-4-fluoro-L-prolyl]azetidin-3-yl)oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 92) -   2-hydroxy-7-({1-[(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 93) -   8-[(1-{[(3R,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 94) -   8-[(1-{[(3S,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 95) -   8-[(1-{[(2R,4S)-4-fluoropyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 96)

A reaction, work-up, and purification were performed using the compounds of Reference Examples 82 to 105 and 117 to 123 as the starting materials by the same method described in Example 38 to obtain the following Example compounds 97 to 127 (corresponding starting materials are not in order). However, if hydrochloride is the final product (Examples 119, 120, and 123), the hydrochloride was obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-19 Starting Example material Structural formula NMR and/or LCMS  97 Reference Example  82

LCMS: [M + H]⁺/Rt = 397.3/1.08 min^(B) ¹H-NMR (CD₃OD) δ: 7.63 (1H, d, J = 8.1 Hz), 5.95 (1H, d, J = 8.1 Hz), 5.03-4.95 (1H, m), 4.64-4.52 (1H, m), 4.39-4.25 (2H, m), 4.09-3.95 (2H, m), 3.37-3.01 (2H, m), 2.62-2.20 (4H, m), 0.46 (2H, t, J = 8.1 Hz).  98 Reference Example 117

LCMS: [M + H]⁺/Rt = 377.2/0.65 min^(B) ¹H-NMR (CD₃OD) δ: 6.73 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.02-4.92 (1H, m), 4.62-4.52 (1H, m), 4.42-4.22 (3H, m), 4.08-4.00 (1H, m), 3.92-3.86 (1H, m), 3.22-3.16 (1H, m), 2.80-2.75 (1H, m), 2.57 (2H, t, J = 8.1 Hz), 2.10-2.01 (1H, m), 1.89-1.76 (1H, m), 0.45 (2H, t, J = 8.1 Hz).  99 Reference Example  83

LCMS: [M + H]⁺/Rt = 389.3/0.91 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 4.99-4.89 (1H, m), 4.54-4.48 (1H, m), 4.33-4.19 (2H, m), 4.02-3.97 (1H, m), 3.00-2.95 (2H, m), 2.63-2.53 (4H, m), 2.19 (2H, d, J = 8.1 Hz), 1.99-1.81 (1H, m), 1.73-1.65 (2H, m), 1.33-1.14 (2H, m), 0.43 (2H, t, J = 8.1 Hz). 100 Reference Example  84

LCMS: [M + H]⁺/Rt = 361.2/0.93 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.58-4.52 (1H, m), 4.32-4.25 (2H, m), 4.02-3.97 (1H, m), 3.09-2.76 (5H, m), 2.56 (2H, d, J = 8.1 Hz), 2.03-1.85 (2H, m), 0.43 (2H, t, J = 8.1 Hz).

TABLE 3-20 101 Reference Example 118

LCMS: [M + H]⁺/Rt = 377.2/0.54 min^(B) ¹H-NMR (CD₃OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.04-4.94 (1H, m), 4.60-4.49 (1H, m), 4.40-4.24 (3H, m), 4.10-4.01 (1H, m), 3.72-3.66 (1H, m), 3.01-2.97 (1H, m), 2.81-2.75 (1H, m), 2.56 (2H, d, J = 8.1 Hz), 2.40-2.26 (1H, m), 1.76-1.67 (1H, m), 0.44 (2H, t, J = 8.1 Hz). 102 Reference Example 120

LCMS: [M + H]⁺/Rt = 376.2/0.31 min^(B) ¹H-NMR (CD₃OD) δ: 6.73 (1H, d, J = 8.1 Hz), 5.95 (1H, d, J = 8.1 Hz), 5.02-4.94 (1H, m), 4.61-4.49 (1H, m), 4.38-4.21 (2H, m), 4.09-4.00 (1H, m), 3.75-3.61 (1H, m), 3.49-3.29 (1H, m), 3.00-2.78 (1H, m), 2.56 (2H, d, J = 8.1 Hz), 2.41-2.18 (1H, m), 1.64-1.29 (2H, m), 0.45 (2H, t, J = 8.1 Hz). 103 Reference Example 121

LCMS: [M + H]⁺/Rt = 418.3/0.74 min^(B) ¹H-NMR (CD₃OD) δ: 6.77 (1H, d, J = 8.1 Hz), 5.97 (1H, d, J = 8.1 Hz), 5.02-4.96 (1H, m), 4.62-4.52 (1H, m), 4.40-4.23 (3H, m), 4.10-4.03 (1H, m), 3.76-3.72 (1H, m), 3.02-2.86 (2H, m), 2.57 (2H, d, J = 8.1 Hz), 2.48-2.35 (1H, m), 1.92 (3H, s), 1.75-1.63 (1H, m), 0.54-0.45 (2H, m). 104 Reference Example 119

LCMS: [M + H]⁺/Rt = 377.2/0.55 min^(B) ¹H-NMR (CD₃OD) δ: 6.76 (1H, d, J = 8.1 Hz), 5.98 (1H, d, J = 8.1 Hz), 5.03-4.97 (1H, m), 4.62-4.49 (2H, m), 4.39-4.22 (2H, m), 4.11-4.05 (1H, m), 3.69-3.65 (1H, m), 3.35-3.19 (1H, m), 2.89-2.80 (1H, m), 2.57 (2H, d, J = 8.1 Hz), 2.11-1.80 (2H, m), 0.50-0.42 (2H, m). 105 Reference Example  85

LCMS: [M + H]⁺/Rt = 389.3/1.18 min^(B) ¹H-NMR (CD₃OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.02-4.96 (1H, m), 4.59-4.47 (1H, m), 4.39-4.20 (2H, m), 4.08-4.00 (1H, m), 3.83-3.77 (1H, m), 2.80-2.54 (4H, m), 2.00-1.88 (1H, m), 1.59-1.50 (1H, m), 1.09 (3H, s), 1.06 (3H, s), 0.44 (2H, t, J = 8.1 Hz). 106 Reference Example  86

LCMS: [M + H]⁺/Rt = 375.2/0.99 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.92 (1H, d, J = 8.1 Hz), 4.98-4.91 (1H, m), 4.53-4.47 (1H, m), 4.33-4.19 (2H, m), 4.03-3.96 (1H, m), 3.37-3.33 (1H, m), 3.08-2.80 (2H, m), 2.56 (2H, t, J = 8.1 Hz), 2.35-2.30 (2H, m), 2.06-1.90 (1H, m), 1.85-1.72 (2H, m), 1.43-1.29 (1H, m), 0.42 (2H, t, J = 8.1 Hz).

TABLE 3-21 107 Reference Example 87

LCMS: [M + H]⁺/Rt = 375.3/0.96 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.63-4.52 (1H, m), 4.36-4.22 (2H, m), 4.06-3.96 (1H, m), 3.09-3.02 (1H, m), 2.66-2.53 (3H, m), 1.94-1.75 (2H, m), 1.63-1.27 (5H, m), 0.43 (2H, t, J = 8.1 Hz). 108 Reference Example 88

LCMS: [M + H]⁺/Rt = 375.3/0.99 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 4.99-4.92 (1H, m), 4.60-4.53 (1H, m), 4.31-4.25 (2H, m), 4.01-3.95 (1H, m), 2.95 (2H, t, J = 8.1 Hz), 2.66-2.39 (5H, m), 1.88-1.43 (4H, m), 0.43 (2H, t, J = 8.1 Hz). 109 Reference Example 89

LCMS: [M + H]⁺/Rt = 375.3/0.95 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 4.99-4.90 (1H, m), 4.58-4.53 (1H, m), 4.31-4.25 (2H, m), 4.01-3.96 (1H, m), 3.08-2.99 (2H, m), 2.66-2.40 (5H, m), 1.71-1.51 (4H, m), 0.43 (2H, t, J = 8.1 Hz). 110 Reference Example 90

LCMS: [M + H]⁺/Rt = 362.2/1.31 min^(B) ¹H-NMR (CD₃OD) δ: 6.63 (1H, d, J = 8.1 Hz), 5.84 (1H, d, J = 8.1 Hz), 4.91-4.83 (1H, m), 4.62-4.52 (1H, m), 4.35-4.21 (3H, m), 3.97-3.68 (3H, m), 2.47 (2H, t, J = 8.1 Hz), 2.19-2.01 (1H, m), 1.96-1.71 (3H, m), 0.41-0.31 (2H, m). 111 Reference Example 91

LCMS: [M + H]⁺/Rt = 437.0/1.34 min^(B) ¹H-NMR (CD₃OD) δ: 7.31-7.26 (4H, m), 7.21-7.15 (1H, m), 6.70 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.05-4.94 (1H, m), 4.65-4.54 (1H, m), 4.42-4.26 (2H, m), 4.11-4.03 (1H, m), 3.89 (1H, t, J = 8.1 Hz), 3.77-3.65 (1H, m), 3.39-3.20 (1H, m), 3.07-2.96 (1H, m), 2.85-2.53 (3H, m), 1.94-1.77 (1H, m), 0.42 (2H, t, J = 8.1 Hz). 112 Reference Example 92

LCMS: [M + H]⁺/Rt = 373.3/0.96 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.91 (1H, d, J = 8.1 Hz), 5.00-4.91 (1H, m), 4.54-4.46 (1H, m), 4.36-4.26 (2H, m), 4.05-3.99 (2H, m), 2.77-2.71 (1H, m), 2.58-2.39 (3H, m), 1.95-1.87 (1H, m), 1.52-1.43 (1H, m), 0.63-0.55 (1H, m), 0.48-0.38 (3H, m).

TABLE 3-22 113 Reference Example  93

LCMS: [M + H]⁺/Rt = 375.2/0.85 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.92 (1H, d, J = 8.1 Hz), 5.00-4.92 (1H, m), 4.65-4.55 (1H, m), 4.38-4.26 (2H, m), 4.07-3.99 (1H, m), 3.08-3.02 (1H, m), 2.95-2.88 (1H, m), 2.56 (2H, t, J = 8.1 Hz), 2.30-2.10 (5H, m), 1.88-1.79 (3H, m), 0.43 (2H, t, J = 8.1 Hz). 114 Reference Example  94

LCMS: [M + H]⁺/Rt = 389.3/0.95 min^(B) ¹H-NMR (CD₃OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.97-5.93 (1H, m), 4.96-4.86 (1H, m), 4.63-4.57 (1H, m), 4.31-4.20 (2H, m), 4.02-3.96 (1H, m), 3.00-2.84 (2H, m), 2.62-2.50 (3H, m), 2.35-2.23 (1H, m), 2.09-1.96 (3H, m), 1.89-1.80 (1H, m), 1.74-1.54 (2H, m), 1.26-1.10 (1H, m), 0.43 (2H, t, J = 8.1 Hz). 115 Reference Example  95

LCMS: [M + H]+/Rt = 391.3/0.9 min^(B) ¹H-NMR (CD₃OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.93 (1H, d, J = 8.1 Hz), 5.00-4.80 (1H, m), 4.58-4.49 (1H, m), 4.33-4.21 (2H, m), 4.02-3.98 (1H, m), 3.90-3.76 (2H, m), 3.64-3.51 (1H, m), 2.95-2.47 (6H, m), 2.37-2.29 (1H, m), 2.22-2.12 (1H, m), 0.44 (2H, t, J = 8.1 Hz). 116 Reference Example  96

LCMS: [M + H]⁺/Rt = 361.2/0.84 min^(B) ¹H-NMR (CD₃OD) δ: 6.72 (1H, d, J = 8.1 Hz), 5.94 (1H, d, J = 8.1 Hz), 5.16-5.03 (1H, m), 4.56-4.50 (2H, m), 4.37-4.26 (2H, m), 3.78-3.65 (1H, m), 3.57-3.44 (3H, m), 2.89-2.68 (2H, m), 2.61-2.53 (3H, m), 0.43 (2H, t, J = 8.1 Hz). 117 Reference Example  97

LCMS: [M + H]⁺/Rt = 390.3/0.34 min^(B) ¹H-NMR (CD₃OD) δ: 6.70 (1H, d, J = 8.1 Hz), 5.95-5.91 (1H, m), 5.10-4.97 (1H, m), 4.44-3.61 (4H, m), 3.35-1.52 (10H, m), 0.43 (2H, t, J = 8.1 Hz). 118 Reference Example  98

LCMS: [M + H]⁺/Rt = 389.3/0.98 min^(B) ¹H-NMR (CD₃OD) δ: 6.80-6.73 (1H, m), 5.98-5.91 (1H, m), 5.00-4.76 (1H, m), 4.35-3.79 (4H, m), 3.22-3.00 (3H, m), 2.65-2.51 (2H, m), 2.33-1.29 (8H, m), 0.55-0.28 (2H, m). 119 Reference Example 122

LCMS: [M + H]⁺/Rt = 376.2/0.41 min^(B) ¹H-NMR (CD₃OD) δ: 7.18 (1H, d, J = 8.1 Hz), 6.41-6.30 (1H, m), 5.22-5.10 (1H, m), 4.89-4.69 (2H, m), 4.57-4.26 (2H, m), 4.20-4.05 (2H, m), 3.93-3.86 (1H, m), 3.57-3.47 (1H, m), 2.70 (2H, t, J = 8.1 Hz), 2.64-2.45 (2H, m), 1.07 (2H, t, J = 8.1 Hz).

TABLE 3-23 120 Reference Example 123

LCMS: [M + H]⁺/Rt = 418.2/0.89 min^(B) ¹H-NMR (CD₃OD) δ: 7.18 (1H, d, J = 8.1 Hz), 6.41-6.30 (1H, m), 5.20-5.12 (1H, m), 4.77-4.26 (5H, m), 4.14-4.05 (1H, m), 3.67-3.60 (1H, m), 3.36-3.30 (1H, m), 2.71 (2H, t, J = 8.1 Hz), 2.48-2.21 (2H, m), 1.98 (3H, s), 1.07 (2H, t, J = 8.1 Hz). 121 Reference Example  99

LCMS: [M + H]⁺/Rt = 404.3/0.34 min^(B) ¹H-NMR (CD₃OD) δ: 6.74-6.69 (1H, m), 5.98-5.92 (1H, m), 5.03-4.94 (1H, m), 4.64-4.47 (1H, m), 4.39-4.19 (2H, m), 4.05-3.97 (1H, m), 3.19-2.46 (7H, m), 2.00-1.80 (1H, m), 1.71-1.28 (4H, m), 0.43 (2H, t, J = 8.1 Hz). 122 Reference Example 104

LCMS: [M + H]⁺/Rt = 389.3/1.05 min^(B) ¹H-NMR (CD₃OD) δ: 6.74-6.69 (1H, m), 5.91-5.86 (1H, m), 4.94-4.83 (1H, m), 4.48-3.97 (4H, m), 3.12-2.86 (2H, m), 2.71-2.54 (3H, m), 2.26-2.14 (2H, m), 1.85-1.12 (6H, m), 0.42 (2H, t, J = 8.1 Hz). 123 Reference Example 105

LCMS: [M + H]⁺/Rt = 404.1/0.84 min^(B) ¹H-NMR (CD₃OD) δ: 7.18 (1H, d, J = 8.2 Hz), 6.41-6.31 (1H, m), 5.20-5.10 (1H, m), 4.81-4.64 (1H, m), 4.58-4.42 (2H, m), 4.38-4.25 (1H, m), 4.18-4.05 (1H, m), 3.68-3.50 (2H, m), 3.38-3.26 (1H, m), 2.85-2.67 (3H, m), 2.16-2.06 (1H, m), 1.06 (2H, t, J = 8.1 Hz). 124 Reference Example 100

LCMS: [M + H]+/Rt = 375.2/0.89 min^(B) 1¹H-NMR (CD₃OD) δ: 6.77-6.62 (1H, m), 6.00-5.85 (1H, m), 4.99-4.91 (1H, m), 4.57-4.44 (1H, m), 4.35-4.16 (2H, m), 4.04-3.92 (1H, m), 3.10-2.81 (3H, m), 2.62-2.40 (4H, m), 2.29-2.19 (2H, m), 2.10-1.96 (1H, m), 1.56-1.37 (1H, m), 0.48-0.36 (2H, m). 125 Reference Example 101

LCMS: [M + H]+/Rt = 375.1/0.92 min^(B) ¹H-NMR (CD₃OD) δ: 6.75-6.64 (1H, m), 5.99-5.88 (1H, m), 5.01-4.89 (1H, m), 4.59-4.42 (1H, m), 4.37-4.15 (2H, m), 4.03-3.90 (1H, m), 3.12-2.84 (3H, m), 2.61-2.39 (4H, m), 2.31-2.17 (2H, m), 2.11-1.95 (1H, m), 1.59-1.40 (1H, m), 0.47-0.32 (2H, m). 126 Reference Example 102

LCMS: [M + H]+/Rt = 375.1/0.99 min^(B) ¹H-NMR (CD₃OD) δ: 6.77-6.65 (1H, m), 5.96-5.86 (1H, m), 4.97-4.84 (1H, m), 4.56-3.94 (4H, m), 3.41-3.26 (1H, m), 3.09-2.75 (2H, m), 2.62-2.49 (2H, m), 2.37-2.23 (2H, m), 2.09-1.70 (3H, m), 1.47-1.25 (1H, m), 0.49-0.33 (2H, m).

TABLE 3-24 127 Reference Example 103

LCMS: [M + H]+/Rt = 375.0/0.93 min^(B) ¹H-NMR (CD₃OD) δ: 6.69 (1H, d, J = 8.2 Hz), 5.91 (1H, d, J = 8.2 Hz), 4.98- 4.85 (1H, m), 4.56-4.46 (1H, m), 4.35- 4.17 (2H, m), 4.05-3.94 (1H, m), 3.38- 3.26 (1H, m), 3.03-2.73 (2H, m), 2.61- 2.49 (2H, m), 2.37-2.26 (2H, m), 2.03- 1.88 (1H, m), 1.85-1.67 (2H, m), 1.46- 1.24 (1H, m), 0.46-0.37 (2H, m).

The names of the compounds of Examples 97 to 127 are described below.

-   8-{[1-(4,4-difluoro-L-prolyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo(4.4.0)deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 97) -   4,4-dihydroxy-8-({1-[(4R)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 98) -   4,4-dihydroxy-8-({1-[(piperidin-4-yl)acetyl)azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 99) -   4,4-dihydroxy-8-{(1-(pyrrolidine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 100) -   4,4-dihydroxy-8-({1-[(4S)-4-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 101) -   8-({1-[(4S)-4-amino-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 102) -   8-({1-[(4S)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 103) -   4,4-dihydroxy-8-({1-[(3R)-3-hydroxy-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo([4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 104) -   8-{[1-(4,4-dimethyl-L-prolyl)azetidin-3-yl]oxy}-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 105) -   4,4-dihydroxy-8-({1-[(pyrrolidin-2-yl)acetyl)azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 106) -   4,4-dihydroxy-8-({1-(piperidine-2-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 107) -   4,4-dihydroxy-8-{[1-(piperidine-3-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 108) -   4,4-dihydroxy-8-{[1-(piperidine-4-carbonyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 109) -   4,4-dihydroxy-8-({1-[(2S)-oxolane-2-carbonyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 110) -   4,4-dihydroxy-8-({1-[(4R)-4-phenyl-L-prolyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 111) -   8-({1-[(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 112) -   4,4-dihydroxy-8-{[1-(1-methyl-L-prolyl)azetidin-3-yl]oxy}-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 113) -   4,4-dihydroxy-8-({1-[(piperidin-3-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 114) -   4,4-dihydroxy-8-({1-[(morpholin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 115) -   8-({1-[(azetidin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 116) -   8-({1-[amino(pyrrolidin-3-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 117) -   4,4-dihydroxy-8-({1-[3-(pyrrolidin-2-yl)propanoyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 118) -   7-({1-[(4R)-4-amino-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid dihydrochloride (Example 119) -   7-({1-[(4R)-4-acetamido-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 120) -   8-({1-[amino(piperidin-4-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 121) -   4,4-dihydroxy-8-({1-[(piperidin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 122) -   7-({1-[(4S)-4-carbamoyl-L-prolyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 123) -   4,4-dihydroxy-8-[(1-{[(3R)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 124) -   4,4-dihydroxy-8-[(1-{[(3S)-pyrrolidin-3-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 125) -   4,4-dihydroxy-8-[(1-{[(2R)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 126) -   4,4-dihydroxy-8-[(1-{[(2S)-pyrrolidin-2-yl]acetyl}azetidin-3-yl)oxy]-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 127)

The following Example compounds 128 and 129 were obtained by performing a reaction, work-up, and purification using the compounds of Reference Examples 61 and 126, respectively, as the starting materials by the same method described in Example 36, further dissolving the resulting crude product in water, adding an aqueous 2 N sodium hydroxide solution, and purifying by reversed phase chromatography.

TABLE 3-25 Exam- Starting ple material Structural formula NMR and/or LCMS 128 Reference Example 61

LCMS: [M + H]⁺/Rt = 389.96/0.446 min^(F) ¹H-NMR (D₂O) δ: 6.90 (1H, d, J = 8.2 Hz), 6.07 (1H, d, J = 8.2 Hz), 5.01 (1H, m), 4.60 (1H, m), 4.28-4.40 (2H, m), 4.05 (1H, m), 2.94-3.09 (4H, m), 2.58-2.81 (4H, m), 2.45 (1H, m), 2.22-2.31 (2H, m), 0.38 (2H, m). 129 Reference Example 126

LCMS: [M + H]⁺/Rt = 438.95/0.555 min^(F) ¹H-NMR (D₂O) δ: 6.90 (1H, d, J = 8.2 Hz), 6.07 (1H, d, J = 8.2 Hz), 5.03 (1H, m), 4.65 (1H, m), 4.42-4.32 (2H, m), 4.08 (1H, m), 3.60 (1H, m), 3.47- 3.12 (5H, m), 2.96-2.79 (2H, m), 2.60 (2H, m), 2.40 (1H, m), 0.39 (2H, m).

The names of the compounds of Examples 128 and 129 are described below.

-   4,4-dihydroxy-8-({1-[(piperazin-2-yl)acetyl]azetidin-3-yl}oxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 128) -   8-({1-[(1,1-dioxo-1λ¹-thiomorpholin-2-yl)acetyl]azetidin-3-yl}oxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylic     acid disodium salt (Example 129)

The following Example compounds 130 to 137 were obtained by performing a reaction, work-up, and purification using the compounds of Reference Examples 128 and 131 to 137 as the starting materials (corresponding starting materials are not in order) by the same method described in Example 38, purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-26 Exam- Starting ple material Structural formula NMR and/or LCMS 130 Reference Example 131

LCMS: [M + H]⁺/Rt=406.1/0.86 min^(B) ¹H-NMR (CD₃OD) δ: 7.19-7.11 (1H, m), 6.36-6.14 (1H, m), 5.16- 4.99 (1H, m), 4.74-4.65 (1H, m), 4.54-4.27 (2H, m), 4.12-3.96 (2H, m), 3.42-3.20 (2H, m), 2.73-2.54 (2H, m), 2.11-1.89 (5H, m), 1.09-0.68 (2H, m). 131 Reference Example 132

LCMS: [M + H]⁺/Rt = 378.1/0.54 min^(B) ¹H-NMR (CD₃OD) δ: 7.19-7.11 (1H, m), 6.34-6.10 (1H, m), 5.13- 4.99 (1H, m), 4.66-4.52 (1H, m), 4.47-4.01 (4H, m), 2.94-2.50 (4H, m), 1.09-0.64 (2H, m). 132 Reference Example 133

LCMS: [M + H]⁺/Rt = 406.1/0.94 min^(B) ¹H-NMR (CD₃OD) δ: 7.18-7.10 (1H, m], 6.64-6.09 (1H, m), 5.14- 5.03 (1H, m), 4.80-4.66 (1H, m), 4.46-4.27 (3H, m), 4.04-3.87 (2H, m), 2.80-2.52 (2H, m), 1.51-1.46 (3H, m), 1.36-1.33 (3H, m), 1.09-0.65 (2H, m). 133 Reference Example 135

LCMS: [M + H]⁺/Rt = 392.1/ 0.88 min^(B) ¹H-NMR (CD₃OD) δ: 7.17 (1H, d, J = 8.1 Hz), 6.39-6.28 (1H, m), 5.17-5.06 (1H, m), 4.99-4.80 (1H, m), 4.73-3.94 (4H, m), 3.74-3.67 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 1.34 (3H, d, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz). 134 Reference Example 136

LCMS: [M + H]⁺/Rt = 450.1/ 0.92 min^(B) ¹H-NMR (CD₃OD) δ: 8.67-8.56 (1H, m), 7.18-7.10 (1H, m), 6.34- 6.10 (1H, m), 5.13-5.05 (1H, m), 4.93-4.66 (1H, m), 4.52-4.27 (3H, m), 4.23-4.13 (1H, m), 4.04-3.95 (1H, m), 3.08-2.52 (4H, m), 1.36-1.33 (3H, m), 1.09- 0.66 (2H, m). 135 Reference Example 134

LCMS: [M + H]⁺/Rt = 449.1/ 0.85 min^(B) ¹H-NMR (CD₃OD) δ: 7.17 (1H, d, J = 8.1 Hz), 6.38-6.28 (1H, m), 5.15-5.05 (1H, m), 4.92-4.64 (1H, m), 4.47-4.27 (3H, m), 4.22-4.15 (1H, m), 4.03-3.95 (1H, m), 2.96-2.86 (1H, m), 2.76- 2.65 (3H, m), 1.34 (3H, d, J = 5.4 Hz), 1.07 (2H, t, J = 8.1 Hz).

TABLE 3-27 136 Reference Example 128

LCMS: [M + H]⁺/Rt = 422.1/0.88 min^(B) ¹H-NMR (CD₃OD) δ: 8.84-8.56 (1H, m), 7.18-7.10 (1H, m), 6.34- 6.09 (1H, m), 5.13-4.59 (2H, m), 4.51-4.26 (3H, m), 4.13- 3.77 (4H, m), 2.79-2.51 (2H, m), 1.37-1.33 (3H, m), 1.09-0.64 (2H, m). 137 Reference Example 137

LCMS: [M + H]⁺/Rt = 379.0/0.71 min^(B) ¹H-NMR (CD₃OD) δ: 7.17 (1H, d, J = 8.2 Hz), 6.78-6.32 (1H, m), 5.14-5.04 (1H, m), 4.67-4.61 (1H, m), 4.47-4.38 (1H, m), 4.31-4.22 (2H, m), 4.05-3.61 (1H, m), 3.00-2.78 (2H, m), 2.70 (2H, t, J = 8.1 Hz), 1.06 (2H, t, J = 8.1 Hz).

The names of the compounds of Examples 130 to 137 are described below.

-   7-({1-[(2S)-4-acetamido-2-aminobutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 130) -   7-{[1-(L-α-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 131) -   7-{[1-(L-alanyl-L-alanyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 132) -   7-([1-(glycyl-D-alanyl)azetidin-3-yl]oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 133) -   N-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-α-asparagine     hydrochloride (Example 134) -   N¹-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-aspartamide     hydrochloride (Example 135) -   N-[(2R)-1-{3-[(8-carboxy-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-7-yl)oxy]azetidin-1-yl}-1-oxopropan-2-yl]-D-serinamide     hydrochloride (Example 136) -   7-({1-[(3S)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 137)

The compounds of Reference Examples 138 and 139 were used as the starting materials to perform a reaction and work-up by the same method described in Example 4. Each of Example compounds 138 and 139 were obtained from purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-28 Exam- Starting ple material Structural formula NMR and/or LCMS 138 Reference Example 138

LCMS: [M + H]⁺/Rt = 401.26/ 0.58 min^(I) ¹H-NMR (500 MHz, CD₃OD) δ: 9.10-9.07 (1H, m), 7.93 (brs, 1H), 7.15 (1H, d, J = 8.0 Hz), 6.37- 6.22 (1H, m), 5.61-5.54 (1H, m), 5.16-4.75 (2H, m), 4.61-3.76 (3H, m), 2.74-2.69 (5H, m), 1.06 (2H, t, J = 8.0 Hz). 139 Reference Example 139

LCMS: [M + H]⁺/Rt = 415.25/ 1.03 min^(I) ¹H-NMR (500 MHz, CD₃OD) δ: 8.91 (1H, brs), 7.95 (1H, brs), 7.14 (1H, d, J = 8.0 Hz), 6.38- 6.23 (1H, m), 5.75-5.58 (1H, m), 5.16-3.94 (6H, m), 3.01-3.81 (5H, m), 2.75-2.65 (5H, m), 1.06 (2H, t, J = 8.0 Hz).

The names of the compounds of Examples 138 and 139 are described below.

-   2-hydroxy-7-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid dihydrochloride (Example 138) -   2-hydroxy-7-({1-[(1H-imidazol-4-yl)(methylamino)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid dihydrochloride (Example 139)

Example 140: 2-hydroxy-7-{[1-(2-methyl-D-seryl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid

A reaction, work-up, and purification were performed using the compound of Reference Example 140 (245 mg, 0.317 mmol) as the starting material by the same method described in Example 36 to obtain the title compound (21.8 mg) as a white solid.

¹H-NMR (0.1M HCl in CD₃OD) δ: 7.18 (1H, d, J=8.5 Hz), 6.35 (1H, d, J=8.5 Hz), 5.14-5.10 (2H, m), 4.50-4.43 (2H, m), 4.12-4.04 (1H, m), 3.91 (1H, d, J=12.2 Hz), 3.72 (1H, d, J=12.2 Hz), 2.70 (2H, t, J=7.6 Hz), 1.52 (3H, s), 1.05 (2H, t, J=7.6 Hz).

LCMS: [M+H]⁺/Rt=365.09/0.447 min^(C)

The following Example compounds 141 to 148 were obtained by performing a reaction using the compounds of Reference Examples 141, 143, and 150 to 155, respectively, as the starting materials by the same method described in Example 36, followed by, as a work-up, concentrating a reaction mixture under reduced pressure and then purifying the mixture by reversed phase chromatography (Column: YMC-Actus pro C18, solution A: 0.05% TFA/water, solution B: 0.03% TPA/acetonitrile). However, if hydrochloride is the final product (Example 145), the hydrochloride was obtained from purifying the compound by reversed phase chromatography, followed by addition of hydrochloric acid and concentration.

TABLE 3-29 Exam- Starting ple material Structural formula NMR and/or LCMS 141 Reference Example 141

LCMS: [M + H]⁺/Rt = 365/1.414 min^(G) ¹H-NMR (D₂O) δ: 7.08-6.89 (1H, m), 6.14-5.94 (1H, m), 4.96-4.67 (2H, m), 4.36-4.29 (2H, m), 4.02-3.92 (1H, m), 3.81-3.73 (1H, m), 3.63- 3.56 (1H, m), 2.52-2.25 (2H, m), 1.38- 1.33 (3H, m), 0.92-0.43 (2H, m). 142 Reference Example 143

LCMS: [M + H]⁺/Rt = 404/1.400 min^(G) ¹H-NMR (D₂O) δ: 7.11-6.91 (1H, m), 6.15-5.89 (1H, m), 4.95-4.81 (1H, m), 4.48-4.38 (1H, m), 4.32-3.84 (4H, m), 3.57-3.39 (3H, m), 3.36-3.29 (1H, m), 2.99-2.67 (2H, m), 2.53-2.36 (2H, m), 0.94-0.45 (2H, m). 143 Reference Example 150

LCMS: [M + H]⁺/Rt = 407/1.175 min^(G) ¹H-NMR (D₂O) δ: 7.09-6.89 (1H, m), 6.15-5.91 (1H, m), 4.94-4.63 (2H, m), 4.50-3.84 (4H, m), 2.53-2.33 (6H, m), 1.92-1.74 (2H, m), 0.93-0.43 (2H, m). 144 Reference Example 151

LCMS: [M + H]⁺/Rt = 379/1.400 min^(G) ¹H-NMR (D₂O) δ: 6.94-6.80 (1H, m), 5.98-5.78 (1H, m), 4.35-3.36 (6H, m), 2.67 (2H, s), 2.35-2.20 (2H, m), 0.91- 0.60 (2H, m).

TABLE 3-30 145 Reference Example 152

LCMS: [M + H]⁺/Rt = 393/1.217 min^(G) ¹H-NMR (D₂O) δ: 7.05-6.84 (1H, m), 6.13-5.85 (1H, m), 4.91-4.71 (1H, m), 4.47-3.87 (5H, m), 2.52-2.21 (4H, m), 2.01 (2H, brs), 0.91-0.40 (2H, m). 146 Reference Example 153

LCMS: [M + H]⁺/Rt = 406/1.223 min^(G) ¹H-NMR (D₂O) δ: 7.05-6.82 (1H, m), 6.14-5.87 (1H, m), 4.92-4.74 (1H, m), 4.28-4.03 (4H, m), 3.46 (1H, brs), 2.50-1.74 (8H, m), 0.92-0.39 (2H, m). 147 Reference Example 154

LCMS: [M + H]⁺/Rt = 378/1.208 min^(G) ¹H-NMR (D₂O) δ: 7.02-6.82 (1H, m), 6.08-5.83 (1H, m), 4.88-4.71 (1H, m), 4.39-3.83 (5H, m), 2.68 (2H, brs), 2.52-2.16 (2H, m), 0.70-0.37 (2H, m). 148 Reference Example 155

LCMS: [M + H]⁺/Rt = 392/1.171 min^(G) ¹H-NMR (D₂O) δ: 7.07-6.81 (1H, m), 6.10-5.84 (1H, m), 4.78-4.67 (1H, m), 4.42-3.80 (5H, m), 2.50-2.33 (2H, m), 2.17 (2H, brs), 1.98-1.96 (2H, m), 0.91-0.38 (2H, m).

The names of the compounds of Examples 141 to 148 are described below.

-   2-hydroxy-7-{[1-(2-methyl-L-seryl)azetidin-3-yl]oxy}-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 141) -   2-hydroxy-7-({1-[(3-oxopiperazin-2-yl)acetyl]azetidin-3-yl}oxy)-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 142) -   7-({1-[(3S)-3-amino-5-carboxypentanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 143) -   7-({1-[(3R)-3-amino-3-carboxypropanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 144) -   7-({1-[(4R)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 145) -   7-({1-[(3S)-3,6-diamino-6-oxohexanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 146) -   7-{[1-(D-α-asparaginyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 147) -   7-{[1-(D-α-glutaminyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid trifluoroacetate (Example 148)

The following Example compounds 149 and 150 were obtained by performing a reaction and work-up using the compounds of Reference Examples 146 and 147, respectively, as the starting materials by the same method described in Example 38, and purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-31 Exam- Starting ple material Structural formula NMR and/or LCMS 149 Reference Example 146

LCMS: [M + H]+/Rt = 393.1/ 0.86 min^(B) 1H-NMR (CD3OD) δ: 7.22-7.08 (1H, m), 6.38-6.06 (1H, m), 5.13-5.01 (1H, m), 4.67-4.52 (1H, m), 4.47-4.32 (1H, m), 4.28-4.18 (1H, m), 4.11-3.92 (2H, m), 2.76-2.62 (2H, m), 2.53-2.38 (2H, m), 2.28-2.04 (2H, m), 1.13-0.61 (2H, m). 150 Reference Example 147

LCMS: [M + H]⁺/Rt = 392.1/ 0.86 min^(B) 1H-NMR (CD3OD) δ: 7.24-7.08 (1H, m), 6.41-6.07 (1H, m), 5.14-5.00 (1H, m), 4.67-4.51 (1H, m), 4.46-4.32 (1H, m), 4.29-4.16 (1H, m), 4.08-3.88 (2H, m), 2.81-2.50 (2H, m), 2.49-2.34 (2H, m), 2.21-2.02 (2H, m), 1.14-0.64 (2H, m).

The names of the compounds of Examples 149 and 150 are described below.

-   7-({1-[(4S)-4-amino-4-carboxybutanoyl]azetidin-3-yl}oxy)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 149) -   7-{[1-(L-α-glutaminyl)azetidin-3-yl]oxy}-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 150)

The following Example compounds 151 and 152 were obtained by performing a reaction and work-up using the compounds of Reference Examples 148 and 149, respectively, as the starting materials by the same method described in Example 4 and purifying the compound by reversed phase chromatography without sodium hydroxide treatment, followed by addition of hydrochloric acid and concentration.

TABLE 3-32 Exam- Starting ple material Structural formula NMR and/or LCMS 151 Reference Example 148

LCMS: [M + H]⁺/Rt = 365.24/ 1.27 min^(I). ¹H-NMR (500 MHz, CDCl₃) δ: 7.18-7.09 (1H, s), 6.32 (1H, brs), 5.13-5.07 (1H, m), 4.78-4.69 (1H, m), 4.50-4.29 (2H, m), 4.10-3.96 (2H, m), 3.81-3.78 (1H, m), 2.67 (2H, t, J = 7.4 Hz), 1.26 (3H, t, J = 5.7 Hz), 1.03 (2H, t, J = 8.1 Hz). 152 Reference Example 149

LCMS: [M + H]⁺/Rt = 365.24/ 1.23 min^(I). ¹H-NMR (500 MHz, CDCl₃) δ: 7.17-7.10 (1H, s), 6.33 (1H, brs), 5.12-5.07 (1H, m), 4.76-4.70 (1H, m), 4.51-4.30 (2H, m), 4.09-3.78 (3H, m), 2.67 (2H, brs), 1.26 (3H, t, J = 6.3 Hz), 1.03 (2H, t, J = 8.0 Hz).

The names of the compounds of Examples 151 and 152 are described below.

-   2-hydroxy-7-[(1-D-threonylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 151) -   2-hydroxy-7-[(1-L-threonylazetidin-3-yl)oxy]-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic     acid hydrochloride (Example 152)

Pharmacological testing methods and results thereof for representative compounds of the invention are shown hereinafter, but the present invention is not limited to the Test Examples.

Test Example 1

Evaluation of minimum inhibitory concentration (MIC) of MEPM against N-lactamase producing bacteria

To evaluate the β-lactamase inhibitory activity of test compounds, the effect of combination of a test compound and a β-lactam agent against β-lactamase producing bacteria was evaluated. Meropenem (MEPM) was used as a β-lactam antimicrobial agent. The minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria when a test compound was added at a fixed concentration (4 μg/mL) was measured by broth microdilution method (common ratio: 2). MIC of MEPM decreasing to less than 1/32 in combination with a test compound is indicated by A, decreasing from 1/32 to 1/16 is indicated by B, decreasing from ⅛ to ¼ is indicated by C, and decreasing to ½ or others are indicated by D. “-” represents untested cases.

TABLE 4 E. coli K. pneumoniae K. pneumoniae Example ATCC BAA-2340 ATCC BAA-2344 ATCC BAA-2524 number (KPC) (KPC) (OXA-48) 1 A A B 2 A A B 3 A A B 4 A A A 5 A B C 6 A A B 7 A A B 8 A A B 9 A A A 10 A A B 11 A B B 12 A A B 13 A A B 14 A A B 15 A A B 16 A — B 17 A B B 18 A A B 19 A A B 20 A B B 21 A B C 22 A A B 23 — A B 24 A A B 25 A A B 26 A A A 27 — A B 28 A A B 29 — A B 30 — A B 31 — A B 32 — A B 33 — A B 34 — A B 35 A A B

Test Example 2

Evaluation of minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria

In the same manner as Test Example 1, E. coli ATCC BAA-2469 (NDM-1), K. pneumomiae ATCC BAA-2470 (NDM-1), K. pneumomiae NCTC 13439 (VIM-1), K. pneumomiae NCTC 13440 (VIM-1), E. coli NCTC 13476 (IMP), and the like can be used to evaluate metallo-β-lactamase inhibitory activity of test compounds.

Test Example 3

Evaluation of minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria

To evaluate the β-lactamase inhibitory activity of test compounds, the effect of combination of a test compound and a β-lactam agent against β-lactamase producing bacteria was evaluated. Meropenem (MEPM) was used as a β-lactam antimicrobial agent. The minimum inhibitory concentration (MIC) of MEPM against β-lactamase producing bacteria when a test compound was added at a fixed concentration (4 μg/mL) was measured by broth microdilution method (common ratio: 2).

The numerical value of (MIC of MEPM in combination with a test compound)/(MIC of MEPM alone) are shown below (“-” represents untested cases).

TABLE 5 E. coli K. pneumoniae K. pneumoniae Example ATCC BAA-2340 ATCC BAA-2344 ATCC BAA-2524 number (KPC) (KPC) (OXA-48) 1 0.031/8 0.063/32 0.063/1 2 0.031/8 0.031/32 0.063/1 3 0.031/8 0.063/32 0.063/1 4 0.016/4 0.031/32 0.031/2 5 0.125/8 2/32 0.125/1 6 0.031/4 0.125/32 0.063/1 7 0.031/4 0.031/32 0.063/1 8 0.031/8 0.063/32 0.063/2 9 0.016/4 0.063/32 0.031/2 10 0.031/4 0.063/32 0.063/2 11 0.063/4 2/32 0.063/1 12 0.031/4 0.063/32 0.063/1 13 0.031/8 0.063/32 0.063/2 14 0.031/8 0.125/32 0.063/2 15 0.031/8 0.063/32 0.063/1 16 0.031/8 0.0125/32 0.063/1 17 0.031/8 2/32 0.063/1 18 0.016/8 0.031/32 0.063/2 19 0.16/8 0.031/32 0.063/2 20 0.031/8 2/32 0.063/1 21 0.125/8 2/32 0.125/1 22 0.016/8 0.031/32 0.063/2 23 — 0.063/32 0.063/2 24 0.016/8 0.5/32 0.063/2 25 0.016/8 0.063/32 0.063/2 26 0.16/8 0.063/32 0.031/2 27 — 0.063/32 0.063/2 28 0.016/8 0.031/32 0.063/2 29 — 0.063/32 0.063/2 30 — 0.125/32 0.125/2 31 — 0.063/32 0.063/2 32 — 0.063/32 0.063/2 33 — ≤0.063/32 ≤0.063/1 34 — 0.063/32 0.063/2 35 0.031/4 0.063/32 0.063/1 36 — ≤0.063/16 ≤0.063/1 37 — ≤0.031/16 ≤0.031/1 38 — ≤0.063/16 ≤0.063/2 39 — 1/16 ≤0.063/2 40 — ≤0.063/16 ≤0.063/1 41 — ≤0.063/16 ≤0.063/1 42 — ≤0.063/16 ≤0.063/2 43 — ≤0.063/16 ≤0.063/1 44 — ≤0.063/16 ≤0.063/1 45 — ≤0.063/16 ≤0.063/2 46 — ≤0.063/16 ≤0.063/2 47 — ≤0.063/16 ≤0.063/2 48 — ≤0.063/16 ≤0.063/2 49 — ≤0.063/16 ≤0.063/2 50 — ≤0.063/16 ≤0.063/1 51 — ≤0.063/32 ≤0.063/2 52 — ≤0.063/16 ≤0.063/1 53 — 0.25/16 ≤0.063/1 54 — 0.25/16 ≤0.063/2 55 — ≤0.031/32 ≤0.031/1 56 — 0.25/16 ≤0.031/1 57 — ≤0.063/16 ≤0.063/1 58 — ≤0.063/16 ≤0.063/2 59 — ≤0.063/32 ≤0.063/2 60 — 0.125/32 ≤0.063/2 61 — ≤0.063/16 ≤0.063/2 62 — ≤0.063/16 0.063/2≤ 63 — ≤0.063/16 ≤0.063/2 64 — ≤0.063/16 ≤0.063/2 65 — ≤0.063/16 ≤0.063/2 66 — ≤0.063/16 ≤0.063/2 67 — ≤0.063/16 ≤0.063/2 68 — ≤0.063/16 ≤0.063/1 69 — ≤0.063/16 ≤0.063/1 70 — ≤0.063/16 ≤0.063/2 71 — ≤0.063/16 ≤0.063/1 72 — ≤0.063/16 ≤0.063/1 73 — ≤0.063/16 ≤0.063/2 74 — 0.25/32 0.125/1 75 — 1/32 ≤0.063/1 76 — 4/32 0.25/1 77 — ≤0.063/16 ≤0.063/2 78 — ≤0.063/16 ≤0.063/1 79 — ≤0.063/16 ≤0.063/1 80 — ≤0.063/16 ≤0.063/1 81 — ≤0.063/16 ≤0.063/1 82 — ≤0.063/16 ≤0.063/1 83 — ≤0.063/32 ≤0.063/2 84 — ≤0.063/32 ≤0.063/2 85 — ≤0.063/32 ≤0.063/2 86 — ≤0.063/32 ≤0.063/2 87 — ≤0.063/18 ≤0.063/1 88 — ≤0.063/32 ≤0.063/2 89 — ≤0.063/16 ≤0.063/1 90 — ≤0.063/16 ≤0.063/1 91 — ≤0.063/16 ≤0.063/1 92 — ≤0.063/16 ≤0.063/2 93 — ≤0.063/16 ≤0.063/2 94 — ≤0.063/16 ≤0.063/1 95 — ≤0.063/16 ≤0.063/1 96 — ≤0.063/16 ≤0.063/1 97 — ≤0.063/16 ≤0.063/2 98 — ≤0.063/16 ≤0.063/2 99 — ≤0.063/16 ≤0.063/2 100 — ≤0.063/16 ≤0.063/2 101 — ≤0.063/16 ≤0.063/2 102 — ≤0.063/16 ≤0.063/2 103 — ≤0.063/16 ≤0.063/2 104 — ≤0.063/32 ≤0.063/2 105 — ≤0.063/32 ≤0.063/2 106 — ≤0.063/16 ≤0.063/2 107 — ≤0.063/16 ≤0.063/2 108 — ≤0.063/16 ≤0.063/2 109 — ≤0.063/16 ≤0.063/2 110 — ≤0.063/16 ≤0.063/2 111 — ≤0.063/16 ≤0.063/2 112 — ≤0.063/16 ≤0.063/2 113 — ≤0.063/16 ≤0.063/2 114 — ≤0.063/16 ≤0.063/2 115 — ≤0.063/16 ≤0.063/2 116 — ≤0.063/16 ≤0.063/2 117 — ≤0.063/16 ≤0.063/2 118 — ≤0.063/16 ≤0.063/2 119 — 0.125/16 ≤0.063/1 120 — ≤0.063/16 ≤0.063/1 121 — ≤0.063/16 ≤0.063/2 122 — ≤0.063/16 ≤0.063/2 123 — ≤0.063/32 ≤0.063/2 124 — ≤0.063/16 ≤0.063/2 125 — ≤0.063/16 ≤0.063/2 126 — ≤0.063/16 ≤0.063/2 127 — ≤0.063/16 ≤0.063/2 128 — ≤0.063/16 ≤0.063/1 129 — ≤0.063/16 ≤0.063/1 130 — ≤0.063/16 ≤0.063/1 131 — ≤0.063/16 ≤0.063/1 132 — ≤0.063/16 ≤0.063/1 133 — ≤0.063/16 ≤0.063/1 134 — ≤0.063/16 ≤0.063/1 135 — ≤0.063/16 ≤0.063/1 136 — ≤0.063/16 ≤0.063/1 137 — ≤0.063/16 ≤0.063/2 138 — ≤0.063/16 ≤0.063/2 139 — ≤0.063/16 ≤0.063/2 140 — ≤0.063/64 ≤0.063/2 141 — ≤0.063/64 ≤0.063/2 142 — ≤0.063/64 ≤0.063/2 143 — ≤0.063/64 ≤0.063/2 144 — ≤0.063/64 ≤0.063/2 145 — ≤0.063/64 ≤0.063/2 146 — ≤0.063/64 ≤0.063/2 147 — ≤0.063/64 ≤0.063/2 148 — ≤0.063/64 ≤0.063/2 149 — 0.125/64 ≤0.063/2 150 — ≤0.063/64 ≤0.063/2 151 — ≤0.063/64 ≤0.063/2 152 — ≤0.063/64 ≤0.063/2

As disclosed above, the present invention is exemplified by the use of its preferred embodiments. However, it is understood that the scope of the present invention should be interpreted based solely on the Claims. It is also understood that any patent, any patent application, and any other references cited herein should be incorporated herein by reference in the same manner as the contents are specifically described herein.

INDUSTRIAL APPLICABILITY

The compound of the invention exhibits a potent inhibitory action against β-lactamase and is useful as a therapeutic agent and/or prophylactic agent for sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, or the like, urinary tract infection, genital infection, eye infection, or odontogenic infection. 

1-54. (canceled)
 55. A compound represented by formula (11):

or a pharmaceutically acceptable salt thereof, wherein R^(G) is a hydroxyl group, a thiol group, or —NHR^(a1), G is an oxygen atom, a sulfur atom, or —NR^(a1)—, X is a hydroxyl group, an optionally substituted C₁₋₆ alkoxy group, or —NR^(a2)R^(b1), R^(a1), R^(a2), and R^(b1) are the same or different, each independently 1) a hydrogen atom, 2) a C₁₋₆ alkyl group, 3) a C₃₋₁₀ alicyclic group, 4) C₆₋₁₀ aryl 5) 5- or 6-membered heteroaryl, 6) a 4- to 10-membered non-aryl heterocycle, 7) a C₁₋₆ alkylcarbonyl group, 8) a C₃₋₁₀ alicyclic carbonyl group, 9) a C₆₋₁₀ arylcarbonyl group, 10) a 5- or 6-membered heteroarylcarbonyl group, 11) a C₁₋₆ alkylsulfonyl group, 12) a C₃₋₁₀ alicyclic sulfonyl group, 13) a C₆₋₁₀ arylsulfonyl group, 14) a 5- or 6-membered heteroarylsulfonyl group, or 15) —OR^(c1), wherein each substituent from 2) to 14) is optionally substituted, wherein R^(a2) and R^(b1) together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, R^(c1) is 1) a hydrogen atom 2) a C₁₋₆ alkyl group, 3) a C₃₋₁₀ alicyclic group, 4) C₆₋₁₀ aryl, 5) 5- or 6-membered heteroaryl, or 6) a 4- to 10-membered non-aryl heterocycle, wherein each substituent from 2) to 6) is optionally substituted, L¹ is a single bond, an oxygen atom, a sulfur atom, —SO—, —SO₂—, —NR^(d)—, —NR^(d)C(═O)—, or —NR^(d)SO₂—, L² is a single bond or an optionally substituted C₁₋₆ alkylene group, Z is 1) a hydrogen atom, 2) a hydroxyl group, 3) a cyano group, 4) a carboxyl group, 5) a C₃₋₁₀ alicyclic group, 6) C₆₋₁₀ aryl, 7) 5- or 6-membered heteroaryl, 8) a 4- to 10-membered non-aryl heterocycle, 9) a C₁₋₆ alkoxy group, 10) a C₃₋₁₀ alicyclic oxy group, 11) a C₆₋₁₀ aryloxy group, 12) a 5- or 6-membered heteroaryloxy group, 13) a 4- to 10-membered non-aryl heterocyclyl oxy group, 14) a C₁₋₆ alkylthio group, 15) a C₃₋₁₀ alicyclic thio group, 16) a C₆₋₁₀ arylthio group, 17) a 5- or 6-membered heteroarylthio group, 18) a 4- to 10-membered non-aryl heterocyclyl thio group, wherein each substituent from 5) to 18) is optionally substituted, 19) —SO₂—NR^(e1)R_(f1), 20) —NR^(e1)—C(═O)OR^(f1), 21) —NR^(g1)—C(═O)NR^(e1)R^(f1), 22) —NR^(e1)—C(═S)R^(f1), 23) —NR^(e1)—C(═S)OR^(f1), 24) —NR^(g1)—C(═S)NR^(e1)R^(f1), 25) —NR^(g1)—CR^(e1)(═NR^(f1)), 26) —NR^(g1)—CR^(e1)(═N—OR^(f1)), 27) —NR^(h1)—C(═NR^(g1))NR^(e1)R^(f1), 28) —NR^(h1)—C(═N—OR^(g1))NR^(e1)R^(f1), 29) —NR^(i1)—C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1), 30) —NR^(i1)—C(═N—OR^(h1))NR^(g1)—NR^(e1)R^(f1), 31) —NR^(e1)—SO₂—R^(f1), 32) —NR^(g1)—SO₂—NR^(e1)R^(f1), 33) —C(═O)OR^(e1), 34) —C(═S)OR^(e1), 35) —C(═S)NR^(e1)R^(f1), 36) —C(═S)NR^(e1)OR^(f1), 37) —C(═S)NR^(g1)—NR^(e1)R^(f1), 38) —C(═NR^(e1))R^(f1), 39) —C(═N—OR^(e1))R^(f1), 40) —C(═NR^(h1))NR^(g1)—NR^(e1)R^(f1), 41) —C(°N—OR^(h1))NR^(g1)—NR^(e1)R^(f1), 42) —NR^(e1)R^(f1), 43) —NR^(g1)—NR^(e1)R^(f1), 44) —NR^(e1)OR^(f1), 45) —NR^(e1)—C(═O)R^(f1), 46) —C(═O)NR^(e1)R^(f1), 47) —C(═O)NR^(e1)OR^(f1), 48) —C(═O)NR^(g1)—NR^(e1)R^(f1), 49) —C(═O)R^(e1), 50) —C(═NR^(g1))NR^(e1)R^(f1), or 51) —C(═N—OR^(h1))NR^(e1)R^(f1), one of R¹, R², and R³ is a group represented by formula (2):

wherein Y is an oxygen atom, a sulfur atom, or —NR^(j)—, ring A is an optionally substituted 4- to 20-membered non-aryl heterocycle, L³ is —C(═O)—, —S(═O), or —S(═O)₂—, L⁴ is 1) a single bond, 2) a C₁₋₆ alkylene group, 3) a C₃₋₁₀ cycloalkylene group, 4) a C₆₋₁₀ arylene group, 5) a 5- or 6-membered heteroarylene group, 6) a 4- to 10-membered non-aryl heterocyclylene group, or 7) —C(═N—OR^(h1)), wherein each substituent from 2) to 6) is optionally substituted, and R⁵ is 1) a hydrogen atom 2) a C₁₋₆ alkyl group, 3) a C₃₋₁₀ alicyclic group, 4) a 4- to 10-membered non-aryl heterocycle, 5) C₆₋₁₀ aryl, 6) 5- or 6-membered heteroaryl, 7) a C₁₋₆ alkylthio group, wherein each substituent from 2) to 7) is optionally substituted, or 8) —NR^(e1)OH, the remaining two, which are without the structure of formula (2) among R¹, R² and R³, are the same or different, each independently a hydrogen atom, a halogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkoxy group, an optionally substituted C₁₋₆ (alkylthio group, an optionally substituted 5- or 6-membered heteroaryl, or —NR^(a3)R^(b2), R^(d), R^(e1), R^(e2), R^(f1), R^(f2), R^(g1), R^(g2), R^(h1), R^(h2), R^(i1), R^(i2) and R^(j) are the same or different, each independently a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionally substituted C₃₋₁₀ alicyclic group, optionally substituted C₆₋₁₀ aryl, optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 4- to 10-membered non-aryl heterocycle, a combination of R^(e1) and R^(f1) or R^(e2) and R^(f2), when attached to the same nitrogen atom, together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, R⁴ is 1) —C(═O)R⁸, 2) —SO₂-L⁶-R⁸, wherein R⁸ in 1) and 2) is —NR^(a5)R^(b4), —NR^(a5)-L⁷-B(OR^(m1))₂, —OR^(m1), or an optionally substituted C₁₋₆ alkyl group, and L⁶ is a single bond or —NR^(a6)—, 3) —NR^(a4)R^(b3), 4) —B(OR^(m1)), 5) —PO(OR^(m1))(OR^(m2)), 6) optionally substituted 5-membered heteroaryl, 7) an optionally substituted 5-membered non-aryl heterocycle, or 8) a bioisostere of one of 1) to 7), wherein the formulas of 2), 4), 5), and 6) include a carboxylic acid isostere, and 8) may include them in duplicates, R^(a3), R^(a4), R^(a5), R^(a6), R^(b2), R^(b3), and R^(b4) are the same or different, each independently having the same definition as R^(a1), R^(a2), and R^(b1), wherein a combination of R^(a3) and R^(b2), R^(a4) and R^(b3), or R^(a5) and R^(b4), when attached to the same nitrogen atom, together may form an optionally substituted 4- to 10-membered nitrogen-containing non-aryl heterocycle, R^(m1) is 1) a hydrogen atom, 2) a C₁₋₆ alkyl group, 3) a C₃₋₁₀ alicyclic group, 4) C₆₋₁₀ aryl, 5) 5- or 6-membered heteroaryl, or 6) a 4- to 10-membered non-aryl heterocycle, wherein each substituent from 2) to 6) is optionally substituted, wherein if R^(m1) is attached to a boron atom via an oxygen atom, two R^(m1), as C₂₋₄ alkylene, together with the boron atom and two oxygen atoms, may form a 5- to 7-membered non-aryl heterocycle, wherein an alkylene moiety is optionally substituted in the non-aryl heterocycle, R^(m2) is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, or an optionally substituted C₃₋₁₀ alicyclic group, and L⁷ is an optionally substituted C₁₋₃ alkylene group.
 56. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein the compound of formula (11) is represented by formula (12):


57. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein the compound of formula (12) is represented by formula (13):


58. The compound or the pharmaceutically acceptable salt thereof according to claim 57, wherein X and R^(G) are hydroxyl groups, R⁴ is a carboxyl group, and ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.
 59. The compound or the pharmaceutically acceptable salt thereof according to claim 58, wherein the compound of formula (13) is represented by formula (14):


60. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein R^(G) is a hydroxyl group or a thiol group.
 61. The compound or the pharmaceutically acceptable salt thereof according to claim 60, wherein R^(G) is a hydroxyl group.
 62. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein X is a hydroxyl group or a C₁₋₆ alkoxy group.
 63. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein X is a hydroxyl group.
 64. The compound or the pharmaceutically acceptable salt thereof according to claim 63, wherein m is 1 or 2, n is 1 or 2, and m+n is 2 or
 3. 65. The compound or the pharmaceutically acceptable salt thereof according to claim 64, wherein m is 1, and n is
 1. 66. The compound or the pharmaceutically acceptable salt thereof according to claim 55, wherein L³ is —C(═O)—. 67-69. (canceled)
 70. A medicament comprising the compound or the pharmaceutically acceptable salt thereof according to claim
 55. 71. The medicament according to claim 70, which is a therapeutic drug or a prophylactic drug for a bacterial infection.
 72. A β-lactamase inhibiting agent comprising the compound or the pharmaceutically acceptable salt thereof according to claim 55 as an active ingredient.
 73. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to claim 55 and a pharmaceutically acceptable carrier.
 74. The pharmaceutical composition according to claim 73, further comprising an additional agent.
 75. The pharmaceutical composition according to claim 74, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.
 76. The pharmaceutical composition according to claim 74, wherein the additional agent is a β-lactam agent.
 77. The pharmaceutical composition according to claim 75, wherein the β-lactam agent is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.
 78. The pharmaceutical composition according to claim 77, wherein the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.
 79. The pharmaceutical composition according to claim 77, wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam.
 80. The pharmaceutical composition according to claim 74, wherein the additional agent is included in the pharmaceutical composition such that the additional agent is concomitantly administered with the compound or the pharmaceutically acceptable salt thereof.
 81. The pharmaceutical composition according to claim 80, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.
 82. The pharmaceutical composition according to claim 81, wherein the additional agent is a β-lactam agent.
 83. The pharmaceutical composition according to claim 82, wherein the β-lactam agent is selected from the group consisting of amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethyl penicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin and flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, tomopenem, razupenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicide, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.
 84. The pharmaceutical composition according to claim 83, wherein the β-lactam agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.
 85. The pharmaceutical composition according to claim 83, wherein the β-lactam agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416, and carumonam.
 86. The compound or the pharmaceutically acceptable salt thereof according to claim 55, which is suitable for treating a bacterial infection.
 87. The compound or the pharmaceutically acceptable salt thereof according to claim 86, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.
 88. The compound or the pharmaceutically acceptable salt thereof according to claim 87, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, eye infection, or an odontogenic infection.
 89. A medicament comprising a combination of the compound or the pharmaceutically acceptable salt thereof according to claim 55 and at least one agent selected from the group consisting of therapeutic agents for sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, eye infection, and an odontogenic infection.
 90. (canceled)
 91. A method for treating a bacterial infection, comprising administering a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 55 to a patient in need thereof.
 92. The method according to claim 91, wherein the bacterial infection is a bacterial infection in which a bacteria that can have a β-lactamase is involved.
 93. The method according to claim 92, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of a chronic respiratory disease, pharyngolaryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal abscess, cholecystitis, cholangitis, liver abscess, a deep skin infection, lymphangitis/lymphadenitis, secondary infection of trauma, burn injury, surgical wound, a urinary tract infection, a genital infection, an eye infection, or an odontogenic infection.
 94. The method of claim 93, wherein an additional agent is concomitantly administered. 